bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-Biased Expression Is Associated With Chromatin State in DrosophilamelanogasterandDrosophila simulans
Authors: Nanni Adalena V , Martinez Natalie , Graze Rita , Morse Alison , Newman Jeremy R B , Jain Vaibhav , Vlaho Srna , Signor Sarah , Nuzhdin Sergey V , Renne Rolf , McIntyre Lauren M 
Published: April 2023

AbstractIn Drosophila melanogaster and D. simulans head tissue, 60% of orthologous genes show evidence of sex-biased expression in at least one species. Of these, ∼39% (2,192) are conserved in direction. We hypothesize enrichment of open chromatin in the sex where we see expression bias and closed chromatin in the opposite sex. Male-biased orthologs are significantly enriched for H3K4me3 marks in males of both species (∼89% of male-biased orthologs vs. ∼76% of unbiased orthologs). Similarly, female-biased orthologs are significantly enriched for H3K4me3 marks in females of both species (∼90% of female-biased orthologs vs. ∼73% of unbiased orthologs). The sex-bias ratio in female-biased orthologs was similar in magnitude between the two species, regardless of the closed chromatin (H3K27me2me3) marks in males. However, in male-biased orthologs, the presence of H3K27me2me3 in both species significantly reduced the correlation between D. melanogaster sex-bias ratio and the D. simulans sex-bias ratio. Male-biased orthologs are enriched for evidence of positive selection in the D. melanogaster group. There are more male-biased genes than female-biased genes in both species. For orthologs with gains/losses of sex-bias between the two species, there is an excess of male-bias compared to female-bias, but there is no consistent pattern in the relationship between H3K4me3 or H3K27me2me3 chromatin marks and expression. These data suggest chromatin state is a component of the maintenance of sex-biased expression and divergence of sex-bias between species is reflected in the complexity of the chromatin status.
Induced Immune Reaction in the Acorn Worm, Saccoglossus kowalevskii, Informs the Evolution of Antiviral Immunity
Authors: Tassia Michael G , Hallowell Haley A , Waits Damien S , Range Ryan C , Lowe Christopher J , Graze Rita M , Schwartz Elizabeth Hiltbold , Halanych Kenneth M 
Published: April 2023

Abstract
Evolutionary perspectives on the deployment of immune factors following infection have been shaped by studies on a limited number of biomedical model systems with a heavy emphasis on vertebrate species. Although their contributions to contemporary immunology cannot be understated, a broader phylogenetic perspective is needed to understand the evolution of immune systems across Metazoa. In our study, we leverage differential gene expression analyses to identify genes implicated in the antiviral immune response of the acorn worm hemichordate, Saccoglossus kowalevskii, and place them in the context of immunity evolution within deuterostomes—the animal clade composed of chordates, hemichordates, and echinoderms. Following acute exposure to the synthetic viral double-stranded RNA analog, poly(I:C), we show that S. kowalevskii responds by regulating the transcription of genes associated with canonical innate immunity signaling pathways (e.g., nuclear factor κB and interferon regulatory factor signaling) and metabolic processes (e.g., lipid metabolism), as well as many genes without clear evidence of orthology with those of model species. Aggregated across all experimental time point contrasts, we identify 423 genes that are differentially expressed in response to poly(I:C). We also identify 147 genes with altered temporal patterns of expression in response to immune challenge. By characterizing the molecular toolkit involved in hemichordate antiviral immunity, our findings provide vital evolutionary context for understanding the origins of immune systems within Deuterostomia.
Principles of Cold Adaptation of Fish Lactate Dehydrogenases Revealed by Computer Simulations of the Catalytic Reaction
Authors: Koenekoop Lucien , Åqvist Johan 
Published: April 2023

Abstract
Cold-adapted enzymes from psychrophilic and psychrotolerant species are characterized by a higher catalytic activity at low temperature than their mesophilic orthologs and are also usually found to be more thermolabile. Computer simulations of the catalytic reactions have been shown to be a very powerful tool for analyzing the structural and energetic origins of these effects. Here, we examine the cold adaptation of lactate dehydrogenases from two Antarctic and sub-Antarctic fish species using this approach and compare our results with those obtained for the orthologous dogfish enzyme. Direct calculations of thermodynamic activation parameters show that the cold-adapted fish enzymes are characterized by a lower activation enthalpy and a more negative entropy term. This appears to be a universal feature of psychrophilic enzymes, and it is found to originate from a higher flexibility of certain parts of the protein surface. We also carry out free energy simulations that address the differences in thermal stability and substrate binding affinity between the two cold-adapted enzymes, which only differ by a single mutation. These calculations capture the effects previously seen in in vitro studies and provide straightforward explanations of these experimental results.
Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas
Authors: Gross Andrea M , Dombi Eva , Wolters Pamela L , Baldwin Andrea , Dufek Anne , Herrera Kailey , Martin Staci , Derdak Joanne , Heisey Kara S , Whitcomb Patricia M , Steinberg Seth M , Venzon David J , Fisher Michael J , Kim AeRang , Bornhorst Miriam , Weiss Brian D , Blakeley Jaishri O , Smith Malcolm A , Widemann Brigitte C 
Published: April 2023

Abstract

Background
Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.

Methods
This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index).

Results
For the 74 children (median age 10.3 years; range 3–18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1–100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment.

Conclusions
With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.
Real-world Outcomes Associated With Poly(ADP-ribose) Polymerase Inhibitor Monotherapy Maintenance in Patients With Primary Advanced Ovarian Cancer
Authors: Chan John K. , Liu Jinan , Song Jinlin , Xiang Cheryl , Wu Eric , Kalilani Linda , Hurteau Jean A. , Thaker Premal H. 
Published: April 2023

Objective:
This study used real-world population data to assess the trends of first-line (1L) poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment uptake and outcomes in patients with primary advanced ovarian cancer (AOC).

Methods:
Patients diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemotherapy were selected from a real-world database. Descriptive analyses were performed to evaluate patient demographics, clinicopathological characteristics, and 1L treatment patterns. Time to next treatment or death was used as a proxy for real-world progression-free survival (rwPFS). Kaplan-Meier methods and Cox models were used for statistical analyses.

Results:
Of 705 patients who completed 1L chemotherapy, 166 received PARPi monotherapy and 539 underwent active surveillance (AS). Median follow-up was 10.9 months for PARPi monotherapy and 20.6 months for AS. PARPi monotherapy use increased from 6% in 2017 to 53% in 2021. Overall, patients receiving PARPi monotherapy had longer rwPFS than those who underwent AS (not reached vs 9.53 mo) respectively. rwPFS was also longer in patients who received PARPi monotherapy compared with AS in patients with BRCA-mutated disease (not reached vs 11.4 mo), BRCA–wild-type disease (13.5 vs 9.1 mo), homologous recombination-deficient tumors (not reached vs 10.2 mo), and homologous recombination-proficient or unknown status tumors (13.5 vs 9.3 mo).

Conclusions:
Our real-world analysis suggested that 47% of patients with primary AOC did not receive PARPi maintenance in the year 2021. PARPi use was associated with significantly improved outcomes compared with AS.
Quality of Life in Patients with Acne Vulgaris: an observational study.
Authors: Ruilian Ding , He Yizhen , Wu Qiuju , Lin Tong 
Published: April 2023

Objective:
To investigate the quality of life of patients with acne vulgaris of various degrees of severity, and to provide evidence for establishing effective clinical treatment strategies.

Methods:
We used a self-made questionnaire to assess the demographics, symptoms, and physical signs of patients with acne vulgaris, as well as the acne severity, treatment efficacy, impact of acne on mental health, and effect of acne on daily life. The severity of acne was classified into four grades based on the latest acne grading guideline. Quantitative variables were described as ranges, percentages, and means ± standard deviations. The chi-squared test, linear-by-linear association, and Spearman’s correlation analysis were used to analyze the correlations between categorical variables. Data were analyzed using the Statistical Package for the Social Sciences program (version 22.00; SPSS Inc.). A two-tailed probability value of less than 0.05 was considered statistically significant.

Results:
Of the 94 patients who responded to the questionnaire, the responses of nine patients were excluded because of incomplete data. As the acne severity grading increased and the self-assessed appearance rating decreased, the impacts on daily life, social activity, and mental health increased. There was a weak correlation between the acne severity grading and self-assessed appearance rating (P=0.020, rs=-0.253). The impact of acne severity on the quality of life was mainly reflected as influences on personal reputation (P=0.016) and recreation and leisure activities (P=0.042); the self-assessed appearance mainly affected the patients’ professional careers (P=0.010). The severity of acne (P=0.005) and the effects of acne on attention (P=0.010) and intimacy (P=0.024) varied by sex. Females were less tolerant of appearance blemishes, while males were more troubled by the physical discomforts caused by acne.

Conclusion:
The impact of facial acne on quality of life is related to the acne severity grading, patients’ self-assessed appearance rating, and sex. In clinical practice, therapeutic regimes should be formulated in accordance with the different needs of each patient.
Effectiveness and health benefits of a nutritional, chronobiological and physical exercise primary care intervention in fibromyalgia and chronic fatigue syndrome: SYNCHRONIZE + mixed-methods study protocol
Authors: Carrasco-Querol Noèlia , González Serra Gemma , Bueno Hernández Nerea , Gonçalves Alessandra Queiroga , Pastor Cazalla Marta , Bestratén del Pino Pau , Montesó Curto Pilar , Caballol Angelats Rosa , Fusté Anguera Immaculada , Sancho Sol Mª Cinta , Castro Blanco Elisabet , Vila-Martí Anna , Medina-Perucha Laura , Fernández-Sáez José , Dalmau Llorca M. Rosa , Aguilar Martín Carina 
Published: April 2023

Introduction:
Chronic pain, fatigue and insomnia are classic symptoms of fibromyalgia (FM) and chronic fatigue syndrome (CFS) and seriously affect quality of life. Nutrition and chronobiology are often overlooked in multicomponent approach despite their potential. This study aims to evaluate the effectiveness of a multidisciplinary group intervention based on nutrition, chronobiology, and physical exercise in the improvement of lifestyle and quality of life in FM and CFS.

Methods:
Mixed-methods study based on a randomized clinical trial and qualitative analysis with a descriptive phenomenological approach. The study will be conducted in primary care in Catalonia. The control group will follow the usual clinical practice and the intervention group the usual practice plus the studied intervention (12 hours over 4 days). The intervention based on nutrition, chronobiology and physical exercise will be designed considering participants’ opinions as collected in 4 focus groups. To evaluate effectiveness, EuroQol-5D, multidimensional fatigue inventory, VAS pain, Pittsburgh Sleep Quality Index, erMEDAS-17, biological rhythms interview of assessment in neuropsychiatry, REGICOR-Short, FIQR and Hospital Anxiety and Depression Scale questionnaires will be collected at baseline, and at 1, 3, 6, and 12 months post-intervention. Food intake, body composition, resistance and, strength will also be evaluated. The effect size will be calculated using Cohen d and logistic regression models will be used to quantify the impact of the intervention by adjusting for different variables.

Discussion:
It expected that the intervention will improve the patients’ quality of life, fatigue, pain and insomnia, as well as food and physical exercise habits, providing effectiveness evidence of a new therapy in addressing these syndromes in Primary Heath Care. Improvements in the quality of life will have a positive socioeconomic impact by reducing health expenditure on recurrent medical consultation, medication, complementary medical tests, etc and favor the maintenance of an active working life and productivity.
Network meta-analysis: efficacy and safety of treatments for fistulising Crohn’s disease
Authors: Chahal Jacinder K. , Sriranganathan Danujan , Poo Stephanie , Lo Sheng Wei , Kashkooli Soleiman , Garg Mayur , Segal Jonathan P. 
Published: April 2023

Introduction
Fistulas are a debilitating complication of Crohn’s disease and treatment options remain limited. There is a lack of head-to-head comparisons between treatments. To our knowledge, this is the first network meta-analysis on the efficacy of medical therapies in achieving fistula remission and maintenance of fistula closure in Crohn’s disease.

Methods
Biomedical databases and the Cochrane Central Registry were searched between 1978 and 2022 for randomized controlled trials (RCTs) reporting on treatments. A network meta-analysis was performed using the frequentist model with pooled relative risks (RRs) and P-scores used to rank treatments.

Results
Twenty-five RCTs were included for analysis with 2239 patients included. At the 16–24 week time point, infliximab produced the only statistically significant result with the 5 mg/kg dose proving the most effective [RR, 2.30; 95% confidence interval (CI), 1.40–3.77]. At 44 weeks, ustekinumab was found to be most superior with it being 2.38 times (RR, 2.38; 95% CI, 1.24–4.56) more superior to placebo, with adalimumab (RR, 2.06; 95% CI, 1.06–3.99) and infliximab 5 mg/kg (RR, 1.68; 95% CI, 1.03–2.75) also producing a statistically significant result.

Conclusion
Despite infliximab being favoured in international guidelines for the treatment of perianal fistulising Crohn’s disease, biologics such as ustekinumab, vedolizumab and adalimumab show promising results.
Implications of COVID-19 on hip fracture care discharge locations during the early stages of the pandemic
Authors: Konda Sanjit R. , Esper Garrett W. , Meltzer-Bruhn Ariana T. , Ganta Abhishek , Leucht Philipp , Tejwani Nirmal C. , Egol Kenneth A. 
Published: April 2023

Abstract

Objectives:
To document discharge locations for geriatric patients treated for a hip fracture before and during the COVID pandemic and subsequent changes in outcomes seen between each cohort.

Design:
Retrospective cohort study.

Setting:
Academic medical center.

Patients/Participants:
Two matched cohorts of 100 patients with hip fracture treated pre-COVID (February–May 2019) and during COVID (February–May 2020).

Intervention:
Discharge location and COVID status on admission. Discharge locations were home (home independently or home with health services) versus facility [subacute nursing facility (SNF) or acute rehabilitation facility].

Main Outcome Measurements:
Readmissions, inpatient and 1-year mortality, and 1-year functional outcomes (EQ5D-3L).

Results:
In COVID+ patients, 93% (13/14) were discharged to a facility, 62% (8/13) of whom passed away within 1 year of discharge. Of COVID+ patients discharged to an SNF, 80% (8/10) died within 1 year. Patients discharged to an SNF in 2020 were 1.8x more likely to die within 1 year compared with 2019 (P = 0.029). COVID− patients discharged to an SNF in 2020 had a 3x increased 30-day mortality rate and 1.5x increased 1-year mortality rate compared with 2019. Patients discharged to an acute rehabilitation facility in 2020 had higher rates of 90-day readmission. There was no difference in functional outcomes.

Conclusions:
All patients, including COVID− patients, discharged to all discharge locations during the onset of the pandemic experienced a higher mortality rate as compared with prepandemic. This was most pronounced in patients discharged to a skilled nursing facility in 2020 during the early stages of the pandemic. If this trend continues, it suggests that during COVID waves, discharge planning should be conducted with the understanding that no options eliminate the increased risks associated with the pandemic.

Level of Evidence:
III
Optimizing and validating a pediatric screening tool to more efficiently test and identify children living with HIV
Authors: Joseph Jessica T. , Mpasela Felton , Dowling Stephanie , Banda Isaac , Bobo Patricia M. , Carmone Andy E. , Haimbe Prudence , Hasweeka Pamfred , Kampekete Gertrude S. , Mumba Fredrick , Mwanza Felix , Sakulanda Charles , Simasiku Mwanei , Suggu Kanchana , Shakwelele Hilda , Munthali Gloria 
Published: April 2023

Objective:
To develop and validate a screening tool to improve testing efficiency and increase case finding of children living with HIV.

Design:
Cross-sectional study.

Methods:
Between November 2020 and September 2021, children 18 months to 14 years presenting at outpatient departments in 30 health facilities in Zambia were administered a 14-question pediatric HIV screening tool and then tested for HIV. Data were analyzed using a randomly extracted ‘validation’ dataset and multivariable logistic regression to determine the highest performing and optimal number of screening questions. The final tool was then evaluated in the ‘test’ dataset. Sensitivity and specificity were calculated for both datasets. The final tool was then also implemented in 12 additional facilities to determine operational feasibility and uptake.

Results:
A total of 9,902 children were included in the final analysis. HIV prevalence was 1.3%. Six questions were significantly associated with HIV-positivity. The optimal screening cutoff score was to answer ‘yes’ to one or more of the six questions; using this cutoff sensitivity was 92.5% [95% confidence interval (CI): 85.7%-96.7%] and specificity was 62.9% (95% CI: 61.9%-64.0%). In the test dataset, the same tool had a sensitivity of 84.6% (95% CI: 65.1%-95.6%) and specificity of 64.6% (95% CI: 62.4%-66.7%). Uptake was 89%.

Conclusions:
The results of this study show sensitivity and acceptable specificity in a six-question validated HIV screening tool. Implementing this screening tool in settings where universal testing is not feasible should more efficiently accelerate identification of children living with HIV and their timely initiation onto life-saving drugs.
HIV DNA positively correlates with HLA-DR+CD8+ T lymphocytes over 8-year suppressive ART
Authors: Zhu Tianyuan , Cao Wei , Li Taisheng 
Published: April 2023

Objective:
Despite long-term suppressive cART, the activation level of T lymphocytes remains significantly high HIV-infected individuals. This study aims to unravel the relationship between CD8+ T cell activation and HIV DNA reservoir.

Design/methods:
In this retrospective study, 82 HIV-infected patients receiving suppressive cART for ≥8 years were included. Total HIV-1 DNA and expression of CD38 and HLA-DR in CD8+ T cell were quantified repeatedly during long-term follow-up. Longitudinal correlation between HIV-1 DNA and CD8+ T cell activation level was analysed using generalized estimating equation (GEE) model.

Results:
Significant decrease of both total HIV-1 DNA and CD8+ T cell activation level were observed after combined antiretroviral therapy (cART) initiation. However, the expression level of HLA-DR in CD8+ T cells remained abnormally higher than normal range. GEE analysis revealed that HLA-DR expression was positively correlated with total HIV-1 DNA over long-term suppressive cART.

Conclusions:
HIV DNA reservoir may be closely related to CD8+ T cell activation and the inflammatory state in HIV-infected patients despite long-term cART.