bluuebunny/crossref_metadata_2025 huggingface dataset:
Age and Incidence of Cochlear Implantation in the Pediatric Population With Congenital Bilateral Profound Hearing Loss
Authors: Nassiri Ashley M. , Marinelli John P. , Lohse Christine M. , Carlson Matthew L.
Published: June 2023

Objectives

The current study characterizes age and incidence of cochlear implantation among qualifying children with congenital bilateral profound hearing loss in the U.S.

Study Design

Deidentified cochlear implantation data were acquired from prospectively collected patient registries from two cochlear implant (CI) manufacturers (Cochlear Americas and Advanced Bionics). Children <36 months old were assumed to have congenital bilateral profound sensorineural hearing loss.

Setting

U.S. CI centers.

Patients

Children <36 months old who received CIs.

Interventions

Cochlear implantation.

Main Outcome Measures

Age at implantation and incidence.

Results

A total of 4,236 children <36 months old underwent cochlear implantation from 2015 to 2019. The median age at implantation was 16 months (interquartile range, 12–24 mo) and did not change significantly during the 5-year study period (p= 0.09). Patients residing closer to CI centers (p= 0.03) and treated at higher-volume centers (p= 0.008) underwent implantation at a younger age. Bilateral simultaneous implantation increased from 38% to 53% of CI surgeries in 2015 and 2019, respectively. Children who received bilateral simultaneous CIs were younger compared with those receiving unilateral or bilateral sequential CIs (median, 14 versus 18 mo;p< 0.001). The incidence of cochlear implantation increased from 7,648 per 100,000 person-years in 2015 to 9,344 in 2019 (p< 0.001).

Conclusion

Although the incidence of pediatric CI recipients and the frequency of bilateral simultaneous implantation increased over the study period, age at implantation did not change significantly and far exceeded current Food and Drug Administration (9 mo) and American Academy of Otolaryngology and Head and Neck Surgery position statement (6–12 mo) guidelines.
Clinical Characteristics and Outcomes of Clostridioides difficile Infection in Patients With Left Ventricular Assist Device
Authors: Chesdachai Supavit , Yetmar Zachary A. , Mendoza Maria A. , Ranganath Nischal , Schettle Sarah D. , Boilson Barry A. , Shah Aditya S. , Razonable Raymund R.
Published: June 2023

The literature regarding Clostridioides difficile infection (CDI) in left ventricular assist devices (LVADs) patients is limited. Therefore, we aimed to characterize the clinical course, risk factors, management, and outcomes of LVAD patients who developed CDI. Adult patients who underwent LVAD placement during 2010–2022 and developed CDI were included. To determine risk factors and outcomes, we matched CDI patients with LVAD patients who did not develop CDI. Each CDI case was matched with up to two control subjects by age, sex, and time from LVAD implantation. Forty-seven of 393 LVAD patients (12.0%) developed CDI. The median time from LVAD implantation to CDI was 147 days (interquartile range 22.5–647.0). The most common CDI treatment was oral vancomycin (n = 26, 55.3%). Thirteen patients (27.7%) required treatment extension because of a lack of clinical response. Three patients (6.4%) developed recurrent CDI. When 42 cases were matched to 79 control subjects, antibiotic exposure within 90 days was significantly associated with CDI (adjusted odds ratio 5.77; 95% confidence interval, 1.87–17.74; p = 0.002). Moreover, CDI was associated with 1 year mortality (adjusted hazard ratio 2.62; 95% confidence interval, 1.18–5.82; p = 0.018). This infection occurs most often within the first year after LVAD implantation and was associated with 1 year mortality. Antibiotic exposure is an important risk for CDI.
Comparison of a Novel Binocular Refraction System to Standard Digital Phoropter Refraction
Authors: Bossie Timothy , Reilly Jennifer , Vera-Diaz Fuensanta A.
Published: June 2023

SIGNIFICANCE

New refractive technologies are consistently emerging in the optometry market, necessitating validation against current clinical standards.

PURPOSE

To compare the refractive measurements between standard digital phoropter refraction and the Chronos binocular refraction system.

METHODS

Standardized subjective refraction was conducted on 70 adult participants using two separate refraction systems. The final subjective values from both devices were compared for M, J0, and J45. The time taken to complete refraction and patient’s comfort were also evaluated.

RESULTS

Good agreement was found between the standard and Chronos refraction, with narrow mean differences (including 95% confidence intervals), and no significant bias for M (0.03, -0.05 to 0.11 D), J0 (-0.02, -0.05 to -0.01 D) and J45 (-0.01, -0.03 to 0.01 D). The bounds of the limits of agreement (LoA) of M (lower bound -0.62, -0.76 to -0.49, and upper bound 0.68, 0.54 to 0.81), J0 (lower bound -0.24, -0.29 to -0.19) and upper bound (0.19, 0.15 to 0.24), and J45 (lower bound -0.18, -0.21 to -0.14) and upper bound (0.16, 0.12 to 0.19). No significant differences were noted between the two techniques for any of the refraction components (M standard: -3.03 ± 2.42 D, novel: -3.06 ± 2.37 D, Z = 0.07, P = .47, J0 standard: 0.12 ± 0.40 D, novel: 0.15 ± 0.41 D, Z = 1.32, P = .09, J45 standard: -0.04 ± 0.19 D, novel: -0.03 ± 0.19 D, Z = 0.50, P = .31). The Chronos was significantly faster than the standard technique, with an average difference of 19 seconds (standard: 190 ± 44 seconds, novel: 171 ± 38 seconds, Z = 4.91, P < .001).

CONCLUSIONS

The final subjective refraction endpoints of the standard technique and the Chronos were well aligned in this group of adult participants, and no statistically or clinically significant differences were noted in M, J0 or J45 components. The Chronos offered improved efficiency, meeting the demands of eye care.
Predictive Value of Serum Biomarkers for Response of Limited-Stage AIDS-Associated Kaposi Sarcoma to Antiretroviral Therapy With or Without Concomitant Chemotherapy in Resource-Limited Settings
Authors: Epeldegui Marta , Chang Di , Lee Jeannette , Magpantay Larry I. , Borok Margaret , Bukuru Aggrey , Busakhala Naftali , Godfrey Catherine , Hosseinipour Mina C. , Kang Minhee , Kanyama Cecilia , Langat Deborah , Mngqibisa Rosie , Mwelase Noluthando , Nyirenda Mulinda , Samaneka Wadzanai , Hoagland Brenda , Campbell Thomas B. , Martínez-Maza Otoniel , Krown Susan E. ,   for the A5264/AMC-067 team
Published: June 2023

Background:

Guidelines for limited-stage human immunodeficiency virus-associated Kaposi sarcoma (AIDS/KS) recommend antiretroviral therapy (ART) as initial treatment. However, many such individuals show worsening KS and require additional chemotherapy. Methods to identify such patients are lacking.

Setting:

We studied whether serum levels of biomarkers associated with angiogenesis, systemic inflammation, and immune activation, which are elevated in HIV-infected individuals and implicated in the development of KS, could prospectively identify individuals with limited-stage AIDS-KS who would benefit from chemotherapy administered with ART.

Methods:

Serum specimens were obtained from participants in a randomized trial evaluating the value of adding oral etoposide chemotherapy to ART in treatment-naïve people with limited-stage AIDS-KS in resource-limited settings. Serum biomarkers of inflammation (C-reactive protein [CRP], interleukin [IL]-6, IL-8, IL-10, granulocyte colony stimulating factor, soluble tumor necrosis factor receptor-2), immune system activation (soluble IL-2 receptor alfa, C-X-C motif chemokine ligand 10/interferon gamma-induced protein 10, C–C motif ligand 2/monocyte chemoattractant protein 1), and angiogenesis (vascular endothelial growth factor, matrix metalloproteinase-2, -9, endoglin, hepatocyte growth factor) were measured at entry to determine whether baseline levels are associated with KS response. On-treatment changes in biomarker levels were determined to assess how etoposide modifies the effects of ART.

Results:

Pretreatment CRP and IL-10 were higher in those whose KS progressed, and lowest in those who had good clinical responses. Pretreatment CRP, IL-6, and soluble tumor necrosis factor receptor-2 showed significant associations with KS progression at the week-48 primary endpoint. Immediate etoposide led to lower inflammation biomarker levels compared with ART alone. Early KS progression was associated with elevated pretreatment levels of inflammation-associated biomarkers and increasing levels post-treatment.

Conclusions:

Quantifying serum biomarkers, especially CRP, may help identify persons with AIDS-KS who would benefit from early introduction of chemotherapy in addition to ART.
Telemedicine and HIV Care Quality Measures During the COVID-19 Pandemic
Authors: Masters Mary Clare , Rivera Juan , Calamari Mia , Wright Katherine , Janulis Patrick , Rusie Laura , Bannon Jacqueline , Milne Patrick , Galvin Shannon R. , Molina Elena Gonzalez , Hirschhorn Lisa R. , Palella Frank J. , Kumar Rebecca , Brown Cory , Hawkins Claudia
Published: June 2023

Background:

During the COVID-19 pandemic, telemedicine was adopted to ensure continuity of HIV care. We examined how introducing televisits affected technical quality of care for people with HIV (PWH) during this time.

Methods:

PWH receiving HIV care at Howard Brown Health Centers and Northwestern University in Chicago, Illinois were included. HIV care quality indicators were calculated using data extracted from electronic medical records during 4 timepoints every 6 months from March, March 1, 2020 to September 1, 2021. Generalized linear mixed models estimated differences in indicators across timepoints within each site while controlling for multiple observations of individuals. Generalized linear mixed models were also used to compare differences in outcomes among PWH who attended all versus a combination of in-person and televisits versus no televisits across the study time periods.

Results:

6447 PWH were included in the analysis. Compared with prepandemic levels, there were significant declines in care utilization and processes of care measures. Measures of HIV virologic suppression, blood pressure control, and HbA1C <7% (in both people with and without diabetes) were stable with no significant differences noted across the study timepoints. Similar trends were observed across all age, race, and sex subgroups. In multivariable models, televisits were not associated with decreased HIV viral suppression.

Conclusions:

During the COVID-19 pandemic and rapid implementation of televisits, indicators of care utilization and processes of care decreased compared with prepandemic levels. Among PWH who remained in care, televisits were not associated with worse virologic, blood pressure, and glycemic control in PWH.
Obsessive-Compulsive, Psychotic, and Autism Dimensions Overlap in Real World: A Case Report
Authors: Scala Mauro , Biondi Laura , Serretti Alessandro , Fabbri Chiara
Published: June 2023

Background

Obsessions, compulsions, and stereotypes are common psychopathological manifestations of obsessive-compulsive, psychotic, and autism spectrum disorders (ASDs). These nosological entities may be present in comorbidity, with relevant clinical difficulties in the differential diagnosis process. Moreover, ASDs are a complex group of disorders, with a childhood onset, which also persist into adulthood and present heterogeneous symptom patterns that could be confused with psychotic disorders.

Methods and Results

We report a case of a 21-year-old man characterized by sexual and doubt obsessions; disorganized, bizarre, and stereotyped behaviors and compulsions; and social withdrawal, inadequate social skills, visual dispersions, and hypersensitivity to light stimuli. Obsessive and compulsive features were initially included within the differential diagnosis of psychotic and obsessive-compulsive spectrum disorders. However, aforementioned psychopathological elements did not improve when multiple antipsychotic drugs (olanzapine, haloperidol, and lurasidone) were administered in the hypothesis of schizophrenia and even worsened with clozapine therapy at a dose of 100 mg/d. Obsessions and compulsions progressively reduced during the fluvoxamine 14-week treatment paradigm at a dose of 200 mg/d. Considering the persistent deficits in social communication and interactions as well as the restricted interests pattern, a differential diagnostic hypothesis of ASD was formulated, and it was then confirmed at the final evaluation at a third-level health care center.

Conclusions

We discuss similarities and differences in the psychopathology of obsessions, compulsions, and stereotypes in the previously mentioned disorders, to underline factors that can help in the differential diagnosis of similar cases, and consequently in the appropriateness of treatment choice.
Multicenter Study of Perioperative Hepatic Angioembolization as an Adjunct for Management of Major Operative Hepatic Trauma
Authors: Deville Paige E , Marr Alan B , Cone Jennifer T , Hoefer Lea E , Mitchao Delbrynth P , Inaba Kenji , Kostka Ryan , Mooney Jennifer L , McNickle Allison G , Smith Alison A ,   for the MIT Liver Study Group
Published: June 2023

BACKGROUND:

The management of major liver trauma continues to evolve in trauma centers across the US with increasing use of minimally invasive techniques. Data on the outcomes of these procedures remain minimal. The objective of this study was to evaluate patient complications after perioperative hepatic angioembolization as an adjunct to management of major operative liver trauma.

STUDY DESIGN:

A retrospective multi-institutional study was performed at 13 level 1 and level 2 trauma centers from 2012 to 2021. Adult patients with major liver trauma (grade 3 and higher) requiring operative management were enrolled. Patients were divided into 2 groups: angioembolization (AE) and no angioembolization (NO AE). Univariate and multivariate analyses were performed.

RESULTS:

A total of 442 patients were included with AE performed in 20.4% (n = 90 of 442) of patients. The AE group was associated with higher rates of biloma formation (p = 0.0007), intra-abdominal abscess (p = 0.04), pneumonia (p = 0.006), deep vein thrombosis (p = 0.0004), acute renal failure (p = 0.004), and acute respiratory distress syndrome (p = 0.0003), and it had longer ICU and hospital length of stay (p < 0.0001). On multivariate analysis, the AE had a significantly higher amount intra-abdominal abscess formation (odds ratio 1.9, 95% CI 1.01 to 3.6, p = 0.05).

CONCLUSIONS:

This is one of the first multicenter studies comparing AE in specifically operative high-grade liver injuries and found that patients with liver injury that undergo AE in addition to surgery have higher rates of both intra- and extra-abdominal complications. This provides important information that can guide clinical management.
Breakthrough infections by SARS-CoV-2 variants boost cross-reactive hybrid immune responses in mRNA-vaccinated Golden Syrian Hamsters
Authors: Diego Juan García-Bernalt , Singh Gagandeep , Jangra Sonia , Handrejk Kim , Laporte Manon , Chang Lauren A. , El Zahed Sara S. , Pache Lars , Chang Max W. , Warang Prajakta , Aslam Sadaf , Mena Ignacio , Webb Brett T. , Benner Christopher , García-Sastre Adolfo , Schotsaert Michael
Published: June 2023

Hybrid immunity to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. mRNA vaccine, BNT162b2, was dosed to induce binding antibody titers against ancestral spike, but inefficient serum virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera. Transcriptomics post-infection reflects both vaccination status and disease course and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of high titers of neutralizing antibodies in the serum, correlates with recall of broadly reactive B and T-cell responses.
Observer-rated outcomes of Communication-Centered Treatment (CCT) for adults who stutter: A preliminary study
Authors: Byrd Courtney T. , Coalson Geoffrey A. , Werle Danielle
Published: June 2023

Previous studies have reported that adults who stutter demonstrate significant gains in communication competence, per self-ratings and clinician-ratings, upon completion of a communication-centered treatment, or CCT. The purpose of the present study was to determine whether gains in communication competence would also be reported by untrained observers. Eighty-one untrained observers completed an online survey that required each to view one of two videos depicting an adult who stutters during a mock interview recorded prior to CCT or after CCT. Participants were then asked to rate the communication competence of the interviewee on a 100-point visual analog scale and provide additional demographic information. Communication competence of the adult who stutters was rated significantly higher in their post-treatment video. Two observer-based factors were significantly associated with ratings of communication competence: years of education and years the respondent had known an adult who stutters. Upon controlling for these demographic factors, significantly higher ratings of communication competence for the post-treatment video were maintained. Although preliminary, findings suggest gains in communication competence demonstrated in previous studies through clinician and client observations are not limited to the sterile clinical environment, and further emphasizes the ecological validity of CCT. [ClinicalTrials.govNCT05908123;https://clinicaltrials.gov/show/NCT05908123]
Detecting Full-Length EccDNA with FLED and long-reads sequencing
Authors: Li Fuyu , Ming Wenlong , Lu Wenxiang , Wang Ying , Li Xiaohan , Dong Xianjun , Bai Yunfei
Published: June 2023

Reconstructing the full-length sequence of extrachromosomal circular DNA (eccDNA) from short sequencing reads has proved challenging given the similarity of eccDNAs and their corresponding linear DNAs. Previous sequencing methods were unable to achieve high-throughput detection of full-length eccDNAs. Here we describe a new strategy that combined rolling circle amplification (RCA) and nanopore long-reads sequencing technology to generate full-length eccDNAs. We further developed a novel algorithm, called Full-Length eccDNA Detection (FLED), to reconstruct the sequence of eccDNAs. We used FLED to analyze seven human epithelial and cancer cell line samples and identified over 5,000 full-length eccDNAs per sample. The structures of identified eccDNAs were validated by both PCR and Sanger sequencing. Compared to other published nanopore-based eccDNA detectors, FLED exhibited higher sensitivity. In cancer cell lines, the genes overlapped with eccDNA regions were enriched in cancer-related pathways andcis-regulatory elements can be predicted in the up-stream or downstream of intact genes on eccDNA molecules, and the expressions of these cancer-related genes were dysregulated in tumor cell lines, indicating the regulatory potency of eccDNAs in biological processes. Our method takes advantage of nanopore long reads and enables unbiased reconstruction of full-length eccDNA sequences. FLED is imple-mented using Python3 which is freely available on GitHub (https://github.com/FuyuLi/FLED).
Calcineurin inhibition enhancesCaenorhabditis eleganslifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling
Authors: Das Priyanka , Aballay Alejandro , Singh Jogender
Published: June 2023

Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan ofCaenorhabditis elegansthrough multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) inC. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in theC. elegansDMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.
SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy
Authors: Edelstein Gregory E. , Boucau Julie , Uddin Rockib , Marino Caitlin , Liew May Y. , Barry Mamadou , Choudhary Manish C. , Gilbert Rebecca F. , Reynolds Zahra , Li Yijia , Tien Dessie , Sagar Shruti , Vyas Tammy D. , Kawano Yumeko , Sparks Jeffrey A. , Hammond Sarah P. , Wallace Zachary , Vyas Jatin M. , Barczak Amy K. , Lemieux Jacob E. , Li Jonathan Z. , Siedner Mark J.
Published: June 2023

Objective

To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound.

Design

Observational cohort study.

Setting

Multicenter healthcare system in Boston, Massachusetts.

Participants

We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir.

Exposures

Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy.

Main Outcome and Measures

The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log10copies/milliliter after a prior reduction in viral load to <4.0 log10copies/milliliter.

Results

Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvirritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene.

Conclusions and Relevance

Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.
Healthy adults possess cross-reactive neuraminidase inhibition antibodies to an A(H5N1) clade 2.3.4.4b avian influenza virus A/Black Faced Spoonbill/Hong Kong/AFCD-HKU-22-21429-01012/2022
Authors: Daulagala Pavithra , Cheng Samuel M. S. , Chin Alex W. H. , Luk Leo L. H. , Leung Kathy , Wu Joseph T. , Poon Leo L. M. , Peiris Malik , Yen Hui-Ling
Published: June 2023

Hemagglutination inhibition (HI) and neuraminidase inhibition (NI) antibodies to a clade 2.3.4.4b A(H5N1) highly pathogenic avian influenza virus were measured in 63 age-stratified healthy adults in Hong Kong. No HI antibody was detected; 61 subjects had detectable NI antibodies to A(H5N1). NI titers to A(H5N1) and A(H1N1)pdm09 viruses were correlated.
ecode: An R package to investigate community dynamics in ordinary differential equation systems
Authors: Wu Haoran
Published: June 2023

Population dynamical modelling plays a crucial role in understanding ecological populations and making informed decisions for environmental management. However, existing software packages for dynamical system modelling often lack comprehensive integration of techniques and guidelines, limiting their practical usability. This paper introduces ecode, a novel package for modelling ecological populations and communities using ordinary differential equation systems, designed with a user-friendly framework. By following a three-cycle procedure, users can easily construct ecological models and explore their behaviours through a wide range of graphical, analytical, and numerical techniques. The package incorporates advanced techniques such as grid search methods and simulated annealing algorithms, enabling users to iteratively refine their models and achieve accurate predictions. Notably, ecode minimises external dependencies, ensuring robustness and reducing the risk of package failure caused by updates in dependencies. Overall, ecode serves as a valuable tool for ecological modelling, facilitating the exploration of complex ecological systems and the generation of informed predictions and management recommendations.
Q-BioLiP: A Comprehensive Resource for Quaternary Structure-based Protein–ligand Interactions
Authors: Wei Hong , Wang Wenkai , Peng Zhenling , Yang Jianyi
Published: June 2023

Since its establishment in 2013, BioLiP has become one of the widely used resources for protein–ligand interactions. Nevertheless, several known issues occurred with it over the past decade. For example, the protein–ligand interactions are represented in the form of single chain-based tertiary structures, which may be inappropriate as many interactions involve multiple protein chains (known as quaternary structures). We sought to address these issues, resulting in Q-BioLiP, a comprehensive resource for quaternary structure-based protein–ligand interactions. The major features of Q-BioLiP include: (1) representing protein structures in the form of quaternary structures rather than single chain-based tertiary structures; (2) pairing DNA/RNA chains properly rather than separation; (3) providing both experimental and predicted binding affinities; (4) retaining both biologically relevant and irrelevant interactions to alleviate the problem of the wrong justification of ligands’ biological relevance; and (5) developing a new quaternary structure-based algorithm for the modelling of protein–ligand complex structure. With these new features, Q-BioLiP is expected to be a valuable resource for studying biomolecule interactions, including protein–small molecule, protein–peptide, protein–protein, and protein–DNA/RNA. Q-BioLiP is freely available athttps://yanglab.qd.sdu.edu.cn/Q-BioLiP/.
Follow-Up In Patients With Respiratory Disability After ARDS Related To COVID-19: A Systematic Review
Authors: Triantafyllaki Panagiota , Charalampopoulos Marios , Sampani Christina-Athanasia , Triantafyllou Christos , Papageorgiou Dimitrios
Published: June 2023

Introduction

Acute Respiratory Distress Syndrome (ARDS) is an acute inflammatory pulmonary process that leads to protein-rich, non-hydrostatic pulmonary edema, undesirable hypoxemia, and lung stiffness. Due to COVID-19, a significant proportion of people who will require hospitalization to treat COVID-19, between 15%-30%, will develop severe respiratory failure, ARDS, and an increased likelihood of intubation for mechanical respiratory support.

Aim

To investigate the pulmonary function in COVID-19-related ARDS survivors after hospitalization.

Methods

A search was performed on the Greek and international literature, as well as at the online Databases PubMed, Cochrane, Embase, and Google Scholar. Exclusion and integration criteria were set for the studies found, and a flow chart was created for the studies included.

Results

Through the search, 352 articles were found matching the subject under study, and after further evaluation, four articles were included. The majority of the articles highlight that after ARDS occurs due to COVID-19, patients face impaired pulmonary function in combination with other physical and psychological symptoms like weakness, anxiety, depression, and generalized functional disability.

Conclusions

It is a fact that COVID-19 disease, in severe form and following the need for hospitalization due to the development of ARDS, results in an increased likelihood of prolonged occurrence of some symptoms of impaired respiratory function. Impaired CO2 diffusion is observed in the majority of studies as well as impaired respiratory function regarding prolonged imaging findings and impaired physical function.
Lysosomal mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck
Authors: Gopalkrishnan Avani , Wang Nathaniel , Cruz-Rangel Silvia , Kassab Abdul Yassin- , Shiva Sruti , Kurukulasuriya Chareeni , Monga Satdarshan P. , DeBerardinis Ralph J , Kiselyov Kirill , Duvvuri Umamaheswar
Published: June 2023

Tumor growth and proliferation are regulated by numerous mechanisms. Communication between intracellular organelles has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction) is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. TMEM16A has recently been shown to drive lysosomal biogenesis, but its impact on mitochondrial function is unclear. Here, we show that (1) patients with high TMEM16A SCCHN display increased mitochondrial content specifically complex I; (2)In vitroandin vivomodels uniquely depend on mitochondrial complex I activity for growth and survival; (3) β-catenin/NRF2 signaling is a critical linchpin that drives mitochondrial biogenesis, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that LMI drives tumor proliferation and facilitates a functional interaction between lysosomes and mitochondria. Therefore, inhibition of LMI may serve as a therapeutic strategy for patients with SCCHN.
On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation
Authors: Frey Lukas , Ghosh Dhiman , Qureshi Bilal M. , Rhyner David , Guerrero-Ferreira Ricardo , Pokharna Aditya , Kwiatkowski Witek , Serdiuk Tetiana , Picotti Paola , Riek Roland , Greenwald Jason
Published: June 2023

The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevantin vitrostudies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrilsin vitroas a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8-7.4 a pH- dependent selection between Types 1, 2 and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structurein vitro.
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
Authors: Xu Dongwei , Vincent Alec , González-Gutiérrez Andrés , Aleyakpo Benjamin , Anoar Sharifah , Giblin Ashling , Atilano Magda L , Adams Mirjam , Shen Dunxin , Thoeng Annora , Tsintzas Elli , Maeland Marie , Isaacs Adrian M , Sierralta Jimena , Niccoli Teresa
Published: June 2023

Brains are highly metabolically active organs, consuming 20% of an organisms’ energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it’s unclear if the two are linked.

Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested.

Here, we find that increasing pyruvate import inDrosophilaneurons by over-expression of the transporterbumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer’s disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.
Safety Assessment and Evaluation of Novel Thiourea Derivatives as Antivirals
Authors: Kumar Jitendra , Tyagi Purnima , saini akhilesh kumar , Sharma Deepti , Kumar Vijay
Published: June 2023

DSA-00 and its two derivatives (DSA-02 & DSA-09) are new thiourea derivatives that exhibit strong antiviral activity against hepatitis B virus comparable to Entecavir. Here these compounds were evaluated for in-vitro cytotoxicity and genotoxicity, and in vivo acute toxicity for their potential therapeutic use. The cytotoxicity of thiourea derivatives was assessed in HepG2 and HepG2.2.15 cells by MTT assay whereas their genotoxicity was measured by Ames II test. The acute toxicity study was carried out in the Sprague-Dawley rats by observing the following parameters: mortality, clinical symptoms, hematological parameters, urine and changes in animal body & organs weight, gross necropsy and histopathology. DSA-00, DSA-02, and DSA-09 were non-cytotoxic even at the 320uM concentration with respective CC50 values of 329.6, 323.5, and 349.7 uM. The Ames II test revealed that these molecules were non-mutagenic at a ~1M concentration. The acute toxicity studies revealed LD50 values belong from the moderate range of toxicity of DSA-00, DSA-02 and DSA-09. Importantly, there were no abnormal change in body weight and organs weight. Moreover, no abnormal clinical signs such as hematological parameter, urinalysis, gross necropsy and or histopathological in any of the animals after receiving oral doses of thiourea derivatives. Thiourea derivatives DSA-00, DSA-02, and DSA-09 appear to have a moderate range of acute toxicity at dosages used and thus, appear to be generally safe.
Severe fire regimes decrease resilience of ectothermic populations
Authors: de Sousa Heitor Campos , Malvasio Adriana , Colli Guarino Rinaldi , Salguero-Gómez Roberto
Published: June 2023

Understanding populations’ responses to environmental change is crucial for mitigating human-induced disturbances.

Here, we test hypotheses regarding how three essential components of demographic resilience (resistance, compensation, and recovery) co-vary along the distinct life histories of three lizard species exposed to variable, prescribed fire regimes.

Using a Bayesian hierarchical framework, we estimate vital rates (survival, growth, and reproduction) with 14 years of monthly individual-level data and mark-recapture models to parameterize stochastic Integral Projection Models from five sites in Brazilian savannas, each historically subjected to different fire regimes. With these models, we investigate how weather, microclimate, and ecophysiological traits of each species influence their vital rates, emergent life history traits, and demographic resilience components in varying fire regimes.

Overall, weather and microclimate are better predictors of the species’ vital rates, rather than their ecophysiological traits. Our findings reveal that severe fire regimes increase populations’ resistance, but decrease compensation or recovery abilities. Instead, populations have higher compensatory and recovery abilities at intermediate degrees of fire severity. Additionally, we identify generation time and reproductive output as predictors of resilience trends across fire regimes and climate. Our analyses demonstrate that the probability and quantity of monthly reproduction are the proximal drivers of demographic resilience across the three species.

Our findings suggest that populations surpass a tipping point in severe fire regimes and achieve an alternative stable state to persist. Thus, higher heterogeneity in fire regimes can increase the reproductive aspects and resilience of different populations and avoid high-severity regimes that homogenize the environment. Despite being more resistant, species with long generation times and low reproductive output take longer to recover and cannot compensate as much as species with faster paces of life. We emphasize how reproductive constraints, such as viviparity and fixed clutch sizes, impact the ability of ectothermic populations to benefit and recover from disturbances, underscoring their relevance in conservation assessments.
Development and validation of NAD+metabolism-related gene signature in prognosis prediction of hepatocellular carcinoma
Authors: Du Yiheng
Published: June 2023

Liver cancer is a prevalent and deadly malignancy worldwide, with a rising incidence rate. In this study, we focused on the role of NAD+metabolism-related genes in liver cancer prognosis prediction. We identified key genes among NAD+metabolism-related genes and explored their relationship with cancer staging and prognosis using gene expression data. A risk score model was constructed to assess cancer risk and survival status. The model demonstrated significant predictive potential for survival outcomes. Furthermore, we analyzed the risk scores in different populations and performed functional enrichment analyses to gain insights into the biological processes involved. Our study highlights the clinical value and significance of NAD+metabolism-related genes in liver cancer. The findings provide a foundation for personalized treatment strategies and open new avenues for further research in liver cancer management.
Development and validation of a population pharmacokinetic model to guide perioperative tacrolimus dosing after lung transplantation
Authors: Miano Todd A. , Feng Rui , Griffiths Stephen , Kalman Laurel , Oyster Michelle , Cantu Edward , Yang Wei , Diamond Joshua M. , Christie Jason D. , Scheetz Marc H. , Shashaty Michael G. S.
Published: June 2023

Background

Tacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk time period.

Methods

We conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group (LTOG) cohort. We derived a model in 270 patients using NONMEM (version 7.5.1) and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and multivariable analysis was developed using forward and backward stepwise selection. Performance of the final model in the validation cohort was examined with calculation of mean prediction error (PE).

Results

We developed a one-compartment base model with a fixed rate absorption constant. Significant covariates in multivariable analysis were postoperative day, hematocrit, transplant type,CYP3A5genotype, total body weight, and time-varying postoperative day, hematocrit, and CYP inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than threefold over the 14 day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95%CI 30.8%-41.9%) and a median PE of 7.2% (IQR −29.3%−70.53%).

Conclusion

Postoperative day was the strongest predictor of tacrolimus exposure in the early post-lung transplant period. Future multicenter studies employing intensive sampling to examine a broad set of variables related to critical illness physiology are needed to understand determinants of clearance, volume of distribution and absorption in this population.
Ancient Sheep Genomes reveal four Millennia of North European Short-Tailed Sheep in the Baltic Sea region
Authors: Larsson Martin NA , Miranda Pedro Morell , Pan Li , Başak Vural Kıvılcım , Kaptan Damla , Rodrigues Soares André Elias , Kivikero Hanna , Kantanen Juha , Somel Mehmet , Özer Füsun , Johansson Anna M , Storå Jan , Günther Torsten
Published: June 2023

Sheep are among the earliest domesticated livestock species, with a wide variety of breeds present today. However, it remains unclear how far back this breed diversity goes, with formal documentation only dating back a few centuries. North European short-tailed breeds are often assumed to be among the oldest domestic sheep populations, even thought to represent relicts of the earliest sheep expansions during the Neolithic period reaching Scandinavia less than 6000 years ago. This study sequenced the genomes (up to 11.6X) of five sheep remains from the Baltic islands of Gotland and Åland, dating from Late Neolithic (∼4100 calBP) to historical times (∼1600 CE). Our findings indicate that these ancient sheep largely possessed the genetic characteristics of modern North European short-tailed breeds, suggesting a substantial degree of long-term continuity of this breed type in the Baltic Sea region. Despite the wide temporal spread, population genetic analyses show high levels of affinity between the ancient genomes and they also exhibit higher genetic diversity when compared to modern breeds, implying a loss of diversity in recent centuries associated with breed formation. Finally, we see a potential signature of an even earlier, genetically different form of sheep in Scandinavia as these samples do not represent the first sheep in Northern Europe. Our results shed light on the development of breeds in Northern Europe specifically as well as the development of genetic diversity in sheep breeds, and their expansion from the domestication center in general.
Alternative reproductive tactics and evolutionary rescue
Authors: Knell Robert J , Parrett Jonathan M.
Published: June 2023

Alternative reproductive tactics (ARTs), whereby males within a species exhibit qualitatively different behaviours in their pursuit of matings, are common throughout the animal kingdom. Here, using an individual-based modelling approach, we consider the possible impacts on adaptation and evolutionary rescue arising from one class of ARTs, those expressed through condition-dependent polyphenism such that high-quality, well-adapted males compete aggressively for mates and low-quality, poorly adapted males attempt to acquire matings via other, non-aggressive behaviours. When the ART is simultaneous, meaning that low-quality males do engage in contests but also pursue other tactics, adaptive capacity is reduced and evolutionary rescue, where a population is able to adapt to a changing environment, becomes less likely. This is because the use of the ART allows low-quality males to contribute more maladaptive genes to the population than would happen otherwise. When the ART is fixed, however, such that low-quality males will only use the alternative tactic and do not engage in contests, we find the opposite: adaptation happens more quickly and evolutionary rescue when the environment changes is more likely. This surprising effect results from an increase in the mating success of the highest quality males who face many fewer competitors in this scenario—counterintuitively, the presence of males pursuing the ART increases reproductive skew towards those males in the best condition.
Aneuploidies are an ancestral feature of trypanosomatids, and an ancient chromosome duplication is maintained in extant species
Authors: Reis-Cunha João Luís , Carvalho Samuel Alexandre Pimenta , Almeida Laila Viana , Anderson Coqueiro-dos-Santos A , Marques Catarina De Almeida , Black Jennifer , Damasceno Jeziel , McCulloch Richard , Bartholomeu Daniella Castanheira , Jeffares Daniel Charlton
Published: June 2023

Background

Aneuploidy is widely observed in both unicellular and multicellular eukaryotes, usually associated with adaptation to stress conditions. Chromosomal duplication stability is a tradeoff between the fitness cost of having unbalanced gene copies and the potential fitness gained from increased dosage of specific advantageous genes. Trypanosomatids, a family of protozoans which include species that cause neglected tropical diseases, are a relevant group to study aneuploidies, as their life cycle has several stressors that would benefit from the rapid adaptation provided by aneuploidies.

Results

By evaluating the data from 866 isolates covering 7 Trypanosomatids genera, we have observed that aneuploidies are present in the majority of clades, and have a reduced occurrence in a specific monophyletic clade that has undergone large genomic reorganisation and chromosomal fusions. We have also identified an ancient chromosomal duplication that was maintained across these parasite’s speciations, which has increased sequence diversity, unusual gene structure and expression regulation.

Conclusion

Aneuploidies are an important and ancestral feature in Trypanosomatids. Chromosomal duplication/loss is a constant event in these protozoans, common inLeishmaniaandLeptomonasand repressed inT. bruceiand closely related protozoans. The number of chromosomes with extra copies in a given isolate is usually low, and only one chromosomal duplication was kept for long enough to greatly impact its nucleotide diversity. The thigh control of gene expression in this chromosome suggests that these parasites have adapted to mitigate the fitness cost of having this ancient chromosomal duplication.