bluuebunny/crossref_metadata_2025 huggingface dataset:
Chloroplast Ribosome Biogenesis Factors
Authors: Schmid Lisa-Marie , Manavski Nikolay , Chi Wei , Meurer Jörg
Published: July 2023

The formation of chloroplasts can be traced back to an ancient event in which a eukaryotic host cell containing mitochondria ingested a cyanobacterium. Since then, chloroplasts have retained many characteristics of their bacterial ancestor, including their transcription and translation machinery. In this review, recent research on the maturation of rRNA and ribosome assembly in chloroplasts is explored, along with their crucial role in plant survival and their implications for plant acclimation to changing environments. A comparison is made between the ribosome composition and auxiliary factors of ancient and modern chloroplasts, providing insights into the evolution of ribosome assembly factors. Although the chloroplast contains ancient proteins with conserved functions in ribosome assembly, newly evolved factors have also emerged to help plants acclimate to changes in their environment and internal signals. Overall, this review offers a comprehensive analysis of the molecular mechanisms underlying chloroplast ribosome assembly and highlights the importance of this process in plant survival, acclimation and adaptation.
“It Takes a Village” to Implement Family-Centered Care in the Neonatal Intensive Care Unit
Authors: Kutahyalioglu Nesibe S. , Mallinson R. Kevin , Scafide Katherine N. , D'Agata Amy L.
Published: July 2023

Background:

Although research has demonstrated positive impacts of family-centered care (FCC), many neonatal intensive care unit (NICU) nurses hesitate to fully engage in its practice. There has been little scientific focus on investigating the challenges of FCC implementation in the NICU setting.

Purpose:

The purpose of this study was to generate a grounded theory explaining the process by which neonatal nurses experience facilitators and challenges through engaging in FCC practices in the context of the NICU setting.

Methods:

This qualitative, grounded theory portion of a mixed-methods study employed individual, semistructured, video-based dyadic interviews with 20 neonatal nurses.

Results:

Successful implementation of FCC by neonatal nurses is affected by various factors. The adage that “it takes a village to raise a child” described this process for the nurse participants. The delivery of FCC involves respectful engagement and participation by multiple internal and external stakeholders. The process of delivering FCC was influenced by factors across 6 categories: equitable relationships, bond of trust, knowledge sharing, empowerment in workplace, environment and culture, and regulations. The findings suggest that FCC implementation is not an individual initiative; rather, it involves a complex set of interrelationships between care team members. NICU nurses may consider these findings when they are proposing a change to a FCC model.

Implications for Practice and Research:

Flexibility is necessary by multidisciplinary teams to achieve maximum benefits of FCC and minimize potential harm, despite the unit design. Facilities may support nurses with continuing education programs to expand their FCC knowledge and skills.
Current limits of conservative treatment in ovarian cancer
Authors: Gracia Myriam , Alonso-Espías María , Zapardiel Ignacio
Published: July 2023

Purpose of review

Fertility-sparing surgery in ovarian cancer is an increasing need in gynecology–oncology clinical practice because of the frequent childbearing delay in developed countries. As the evidence in literature is based on observational studies, this review focuses on summarizing the most recent and relevant evidence for the conservative management of young patients with ovarian cancer.

Recent findings

Staging surgery is mandatory in epithelial ovarian tumors. In sex cord-stromal tumors, fertility-sparing surgery is only recommended in FIGO stage IA. Due to its good prognosis, conservative treatment is possible in some cases of advanced disease of germ cell tumors and borderline tumors. Cystectomy is a reasonable option in serous borderline tumors but is not recommended in other tumor subtypes. Successful conception rates after fertility-sparing surgery ranges from 30 to 60%.

Fertility-sparing surgery is a well tolerated option in young women with early-stage ovarian cancer with acceptable reproductive outcomes.
Predicting Hemodynamic Changes During Intra-Aortic Balloon Pump Support With a Longitudinal Evaluation
Authors: Castagna Francesco , Viswanathan Shankar , Chalhoub George , Ippolito Paul , Ovalle Ramos Julio Andres , Vukelic Sasa , Sims Daniel B. , Madan Shivank , Saeed Omar , Jorde Ulrich P.
Published: July 2023

The use of intra-aortic balloon pump (IABP) has decreased in recent years due to negative outcome studies in cardiogenic shock complicating acute myocardial infarction, despite its favorable adverse-event profile. Acute hemodynamic response studies have identified potential super-responders with immediate improvements in cardiac index (CI) in heart failure patients. This single-center retrospective study aimed to predict CI and mean arterial pressure (MAP) changes throughout the entire duration of IABP support. The study analyzed 336 patients who received IABP between 2016 and 2022. Linear mixed-effect regression models were used to predict CI and MAP improvement during IABP support. The results showed that CI and MAP increases during the first days of support, and changes during IABP support varied with time and were associated with baseline parameters. Longitudinal CI change was associated with body surface area, baseline CI, baseline pulmonary artery pulsatility index, baseline need for pressors, and diabetes. Longitudinal MAP change was associated with baseline MAP, baseline heart rate, need for pressors, or inotropes. The study recommends considering these parameters when deciding if IABP is the most appropriate form of support for a specific patient. Further prospective studies are needed to validate the findings.
Air Displacement Plethysmography is an Accurate and Feasible Noninvasive Measure of Fat-Free Mass in Children With Intestinal Failure
Authors: Carey Alexandra N. , Quinn Nicolle , Arouchon Kayla , Elman Daniel M. , Buccigrosso Tess M. , Mitchell Paul D. , Duggan Christopher P.
Published: July 2023

Background:

The nutritional status of children with intestinal failure (IF) can be difficult to determine using body weight and currently available anthropometric techniques. Air displacement plethysmography (ADP) is a noninvasive measure of whole-body composition that measures body mass and volume, with a calculation of percent body fat (%BF) and fat-free mass (FFM) that may be useful during the provision of specialized nutrition.

Objectives:

To evaluate the validity and feasibility of measuring body composition in children with IF using ADP compared with deuterium dilution (DD), as well as secondarily with other measures of body composition, namely bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), and four-site skinfold anthropometry.

Methods:

We conducted a prospective cohort study of 18 children recruited through the Center for Advanced Intestinal Rehabilitation at Boston Children’s Hospital. Patients 2–17 years of age with IF dependent on parenteral nutrition (PN) for more than 90 days were included. Spearman rank correlation and Bland-Altman limits of agreement (LOA) analysis were used to compare ADP to 4 alternative measures of body composition.

Results:

Eighteen children with IF, median age 7.1 [interquartile range (IQR) 5.4–9.3] years, 9 female (50%), and median residual bowel length 31 (IQR 22–85) cm were enrolled. Median PN energy intake was 46 (IQR 39–49) kcal/kg/day. Incomplete bladder emptying lead to invalid measures of DD in 4 subjects. Spearman correlation coefficients for %BF were low to moderate between ADP and DD (r = 0.29), DXA (r = 0.62), BIA (r = 0.50), and skinfold (r = 0.40). Correlations for FFM were high between ADP and these other measures (range 0.95–0.98). Comparing ADP with DD and skinfold measures, Bland-Altman analysis showed small mean bias (−1.9 and +1.5 kg) and acceptable 95% LOA ranges (10.7 and 22.9 kg), respectively, with larger bias (−10.7 and −7.7 kg) and LOA ranges (38.7 and 45.2 kg) compared to DXA and BIA. %BF by ADP and skinfold thickness were moderately correlated (r = 0.43) with low bias (−0.2%) but very wide LOA (25.7%).

Conclusions:

Body composition via ADP is feasible and valid in children with IF as a measure of FFM but appears less suitable for the measurement of %BF. The technique holds promise as a noninvasive measure of body composition to assess the efficacy of nutritional, medical, and surgical interventions.
Descriptive Epidemiology of Pediatric Inflammatory Bowel Disease in Oceania: A Systematic Review and Meta-Analysis
Authors: Forbes Angela J. , Frampton Chris M. A. , Day Andrew S. , Vernon-Roberts Angharad , Gearry Richard B.
Published: July 2023

Objectives:

Pediatric inflammatory bowel diseases (IBDs) are chronic, idiopathic illnesses of the digestive tract, which can impact adversely on children’s quality of life and burden health systems. International studies have shown these diseases are increasing. The aim was to describe pediatric IBD epidemiology across Oceania by conducting a systematic review and meta-analysis of incidence and prevalence.

Methods:

Medline, EMBASE and Web of Science databases were searched in October 2022 for studies reporting rates of IBD, Crohn disease (CD), or ulcerative colitis (UC) in children (≤19 years). Several data collection methodologies were included and pooled estimates of incidence and prevalence were calculated using a random effects model with I
2 measures of heterogeneity.

Results:

Nineteen articles provided 15 incidence and 7 prevalence studies. Fourteen studies were from Australia, 8 studies from New Zealand, and no studies were found from the Pacific Islands. Study dates ranged from 1950 to 2020 with 11 studies using population-based designs. Pooled estimates for annual incidence were IBD 4.1 (3.4–4.8, I
2 = 98.7), CD 2.3 (1.9–2.7, I
2 = 98.6), and UC 0.9 (0.6–1.1, I
2 = 96.8) per 100,000 person-years. Prevalence rates were IBD 36.0 (23.5–48.5, I
2 = 98.4), CD 23.2 (6.6–39.8, I
2 = 97.8), and UC 7.6 (2.7–12.5, I
2 = 99.6) per 100,000 persons.

Conclusions:

Pediatric IBD is prevalent in Oceania with high incidence rates, particularly for CD. Low rates of IBD were observed in indigenous Australian, Māori, and New Zealand Pacific children and there were no studies from the Pacific Islands highlighting this as an area in need of further research.
Progress in muscle strength of the reconstructed knee and quality of life of the patient after knee rotationplasty: A case report
Authors: Fukushima Takuya , Okita Yusuke , Watanabe Noriko , Yokota Shota , Nakano Jiro , Tanaka Yohei , Kawai Akira
Published: July 2023

Knee rotationplasty (KRP) is a function-preserving surgery that serves as an alternative to above-knee amputation in patients diagnosed with malignant bone and soft tissue tumors around the knee joint. However, the short-term progress of the reconstructed knee in terms of muscle strength is unclear after KRP. This case report describes the progress of a 37-year-old man diagnosed with synovial sarcoma in the distal femur, 1 year after undergoing KRP. Changes in muscle strength of the reconstructed knee and physical function are reported. Physical therapy was started on postoperative day 1 after the KRP, and mobilization proceeded step-by-step with sitting, wheelchair transfer, and crutch walking. Active and passive range-of-motion exercises of the reconstructed knee were started on postoperative day 5. The isometric reconstructed knee extension strength, 10-m walk test, timed up and go test, Musculoskeletal Tumor Society score, Toronto Extremity Salvage Score, and quality of life (QOL) were evaluated. One month postoperatively, muscle strength had increased, and at 6 and 12 months postoperatively, isometric knee extension strength and physical function had improved. Furthermore, activities of daily living and QOL gradually improved over the course of the 12 months. Our case shows the previously unknown course of reconstructed knee muscle strength in the early post-KRP period, with corresponding improvements in physical function, activities of daily living, and QOL.
Outcome after Intestinal Transplantation from Living versus Deceased Donors
Authors: Ceulemans Laurens J. , Dubois Antoine , Clarysse Mathias , Canovai Emilio , Venick Robert , Mazariegos George , Vanuytsel Tim , Hibi Taizo , Avitzur Yaron , Hind Jonathan , Horslen Simon , Gondolesi Gabriel , Benedetti Enrico , Gruessner Rainer , Pirenne Jacques
Published: July 2023

Objective:

To describe the worldwide experience with living donation (LD) in intestinal transplantation (ITx) and compare short- and long-term outcome to a propensity-matched cohort of deceased donors.

Summary Background Data:

ITx is a rare life-saving procedure for patients with complicated intestinal failure (IF). Living donation (LD)-ITx has been performed with success but no direct comparison with deceased donation (DD) has been performed. The Intestinal Transplant Registry (ITR) was created in 1985 by the Intestinal Transplant Association to capture the worldwide activity and promote centers collaborations.

Methods:

Based on the ITR, 4156 ITx were performed between January 1987 and April 2019 of which 76 (1.8%) were LD including 5 combined liver-ITx, 7 ITx-colon, and 64 isolated ITx. They were matched with 186 DD-ITx for recipient age/gender, weight, region, IF-cause, re-transplant, pre-transplant status, ABO compatibility, immunosuppression and transplant date. Primary endpoints were acute rejection and 1-/5-year patient/graft survival.

Results:

Most LD were performed in North-America (61%) followed by Asia (29%). Mean recipient age was: 22 years; BMI: 19kg/m²; and female/male ratio: 1/1.4. Volvulus (N=17) and ischemia (N=17) were the most frequent IF-causes. 52% of patients were at home at time of transplant. One-/5-year patient-survival for LD and DD was 74.2/49.8% versus 80.3/48.1%, respectively (P=0.826). One-/5-year graft survival was 60.3/40.6% versus 69.2/36.1%, respectively (P=0.733). Acute rejection was diagnosed in 47% of LD versus 51% of DD (P=0.723).

Conclusion:

Worldwide, LD-ITx has been rarely performed. This retrospective matched ITR analysis revealed no difference in rejection and in patient/graft survival between LD and DD-ITx.
Association Between COVID-19 Vaccination and Mortality after Major Operations
Authors: Sharath Sherene E. , Kougias Panos , Daviú-Molinari Tomás , Faridmoayer Erfan , Berger David H.
Published: July 2023

Background and Objectives:

Societal guidelines recommend postponing elective operations for at least 7 weeks in unvaccinated patients with preoperative COVID-19 infection. The role of vaccination on this infection-operation time risk is unclear. The objective was to compare postoperative, 90-day mortality between (1) fully vaccinated COVID-19 positive and negative patients, and (2) vaccinated and unvaccinated COVID-19 positive patients.

Methods:

We conducted a national US multicenter retrospective, matched-cohort study spanning July 2021 to October 2022. Participants were included if they underwent a high-risk general, vascular, orthopedic, neurosurgery, or genitourinary surgery. All-cause mortality occurring within 90 days of the index operation. Inverse probability treatment weighted (IPTW) propensity scores were used to adjust logistic regression models examining the independent and interactive associations between mortality, exposure status, and infection proximity.

Results:

Of 3,401 fully vaccinated patients in the 8-week preoperative period, 437 (12.9%) were COVID-19 positive. Unadjusted mortality rates were not significantly different between vaccinated COVID-19 patients (22, 5.0%) and vaccinated non-COVID-19 patients (99, 3.3%; P=0.07). After IPTW adjustment, independent mortality risk was not significantly different among vaccinated COVID-19 positive relative to vaccinated COVID-19 negative patients (adjusted Odds Ratio [aOR] = 1.38, 95% CI – 0.70, 2.72). Proximity of COVID-19 diagnosis to the index operation did not confer any added mortality risk in either comparison cohort.

Conclusions and relevance:

Contrary to risks observed among unvaccinated patients, postoperative mortality does not differ between COVID-19 positive and negative patients vaccinated against the SARS-CoV-2 virus and receiving a high-risk operation within 8 weeks of the diagnosis, regardless of operation timing relative to diagnosis.
Quality of Life and Gastrointestinal Symptoms in Long-term Survivors of Pancreatic Cancer Following Pancreatoduodenectomy
Authors: Zhang Chi , Zironda Andrea , Vierkant Robert A. , Starlinger Patrick , Warner Susanne , Smoot Rory , Kendrick Michael , Cleary Sean , Truty Mark , Thiels Cornelius
Published: July 2023

Objective:

To describe long-term quality of life (QOL) and gastrointestinal (GI) symptoms in patients who underwent pancreatoduodenectomy for pancreatic cancer in the modern era.

Summary and Background Data:

As advances in pancreatic cancer management improve outcomes, it is essential to assess long-term patient reported outcomes after surgery.

Methods:

Patients who underwent curative intent pancreatoduodenectomy for pancreatic cancer between 1/2011-6/2019 from a single-center were identified. Patients alive ≥3 years after surgery were considered long-term survivors (LTS). LTS who were alive in 6/2022 received a 55-question survey to assess their QOL (EORTC-QLQ-C30) and GI symptoms (EORTC-PAN26 and Problem Areas in Diabetes Questionnaire). Responses were compared against population norms. Clinicodemographic characteristics in LTS vs non-LTS and survey completion were compared.

Results:

Six-hundred and seventy-two patients underwent pancreatoduodenectomy for pancreatic cancer; 340 were long-term survivors. One-hundred and thirty-seven patients of the 238 eligible to complete the survey responded (response rate: 58%). Compared to the US general population, long-term survivors reported significantly higher QOL (75 vs 64; P<0.001), less nausea/vomiting, pain, dyspnea, insomnia, appetite loss, and constipation, but more diarrhea (all P<0.001). Most patients (n=136/137, 99%) reported experiencing postoperative GI symptoms related to pancreatic insufficiency (n=71/135, 53%), reflux (n=61/135, 45%), delayed gastric emptying (n=31/136, 23%). Most patients (n=113/136, 83%) reported that digestive symptoms overall had little to no impact on QOL, and 91% (n=124/136) would undergo surgery again.

Conclusions:

Despite known long-term complications following pancreatoduodenectomy, cancer survivors appear to have excellent QOL. Specific long-term gastrointestinal symptoms data should be utilized for preoperative education and follow-up planning.
Asymmetry in the peak in Covid-19 daily cases and the pandemic R-parameter
Authors: Bhatkar Sayali , Ma Mingyang , Zsolway Mary , Tarafder Ayush , Doniach Sebastian , Bhanot Gyan
Published: July 2023

Within the context of the standard SIR model of pandemics, we show that the asymmetry in the peak in recorded daily cases during a pandemic can be used to infer the pandemic R-parameter. Using only daily data for symptomatic, confirmed cases, we derive a universal scaling curve that yields: (i) reff, the pandemic R-parameter; (ii) Leff,the effective latency, the average number of days an infected individual is able to infect others and (iii) α, the probability of infection per contact between infected and susceptible individuals. We validate our method using an example and then apply it to estimate these parameters for the first phase of the SARS-Cov-2/Covid-19 pandemic for several countries where there was a well separated peak in identified infected daily cases. The extension of the SIR model developed in this paper differentiates itself from earlier studies in that it provides a simple method to make an a-posteriori estimate of several useful epidemiological parameters, using only data on confirmed, identified cases. Our results are general and can be applied to any pandemic.
Calibrated prediction intervals for polygenic scores across diverse contexts
Authors: Hou Kangcheng , Xu Ziqi , Ding Yi , Harpak Arbel , Pasaniuc Bogdan
Published: July 2023

Polygenic scores (PGS) have emerged as the tool of choice for genomic prediction in a wide range of fields from agriculture to personalized medicine. We analyze data from two large biobanks in the US (All of Us) and the UK (UK Biobank) to find widespread variability in PGS performance across contexts. Many contexts, including age, sex, and income, impact PGS accuracies with similar magnitudes as genetic ancestry. PGSs trained in single versus multi-ancestry cohorts show similar context-specificity in their accuracies. We introduce trait prediction intervals that are allowed to vary across contexts as a principled approach to account for context-specific PGS accuracy in genomic prediction. We model the impact of all contexts in a joint framework to enable PGS-based trait predictions that are well-calibrated (contain the trait value with 90% probability in all contexts), whereas methods that ignore context are mis-calibrated. We show that prediction intervals need to be adjusted for all considered traits ranging from 10% for diastolic blood pressure to 80% for waist circumference. Adjustment of prediction intervals depends on the dataset; for example, prediction intervals for education years need to be adjusted by 90% in All of Us versus 8% in UK Biobank. Our results provide a path forward towards utilization of PGS as a prediction tool across all individuals regardless of their contexts while highlighting the importance of comprehensive profile of context information in study design and data collection.
Comparisons of Heart Rate Variability Responses to Head-up Tilt With and Without Abdominal and Lower-Extremity Compression in Healthy Young Individuals: A Randomized Crossover Study
Authors: Oyake Kazuaki , Katai Miyuki , Yoneyama Anzu , Ikegawa Hazuki , Kani Shigeru , Momose Kimito
Published: July 2023

Introduction

Abdominal and lower-extremity compression techniques can help reduce orthostatic heart rate increase. However, the effects of body compression on the cardiac autonomic systems, which control heart rate, remain unclear. This study aimed to compare heart rate variability, a reflection of cardiac autonomic regulation, during a head-up tilt test with and without abdominal and lower-extremity compression in healthy young individuals.

Methods

In a randomized crossover design, 39 healthy volunteers (20 females, aged 20.9 ± 1.2 years) underwent two head-up tilt tests with and without abdominal and lower-extremity compression. Heart rate and heart rate variability parameters were measured during the head-up tilt tests, including Stress Index, root mean square of successive differences between adjacent R-R intervals, low- and high-frequency components, and low-to-high frequency ratio.

Results

Abdominal and lower-extremity compression reduced the orthostatic increase in heart rate (p < 0.001). The tilt-induced changes in heart rate variability parameters, except for the low-frequency component, were smaller in the compression condition than in the no-compression condition (p < 0.001). Additionally, multiple regression analysis with potentially confounding variables revealed that the compression-induced decrease in Stress Index during the head-up tilt position was a significant independent variable for the compression-induced reduction in heart rate in the head-up tilt position (coefficient = 0.411, p = 0.025). Comparative analyses revealed that abdominal and lower-extremity compression has a notable impact on the compensatory sympathetic activation and vagal withdrawal typically observed during orthostasis, resulting in a reduction of the increase in heart rate. Furthermore, this decrease in heart rate was primarily attributed to the attenuation of cardiac sympathetic activity associated with compression.

Conclusion

Our findings could contribute to the appropriate application of compression therapy for preventing orthostatic tachycardia. This study is registered with UMIN000045179.
The Effects of Virtual Reality Neuroscience-based Therapy on Clinical and Neuroimaging Outcomes in Patients with Chronic Back Pain: A Randomized Clinical Trial
Authors: Čeko Marta , Baeuerle Tassilo , Webster Lynn , Wager Tor D. , Lumley Mark A.
Published: July 2023

Chronic pain remains poorly managed. The integration of innovative immersive technologies (i.e., virtual reality (VR)) with recent neuroscience-based principles that position the brain as the key organ of chronic pain may provide a more effective pain treatment than traditional behavioral therapies. By targeting cognitive and affective processes that maintain pain and potentially directly changing neurobiological circuits associated with pain chronification and amplification, VR-based pain treatment has the potential for significant and long-lasting pain relief.

We tested the effectiveness of a novel VR neuroscience-based therapy (VRNT) to improve pain-related outcomes in n = 31 participants with chronic back pain, evaluated against usual care (n = 30) in a 2-arm randomized clinical trial (NCT04468074). We also conducted pre- and post-treatment MRI to test whether VRNT affects brain networks previously linked to chronic pain and treatment effects. Compared to the control condition, VRNT led to significantly reduced pain intensity (g = 0.63) and pain interference (g = 0.84) at post-treatment vs. pre-treatment, with effects persisting at 2-week follow-up. The improvements were partially mediated by reduced kinesiophobia and pain catastrophizing. Several secondary clinical outcomes were also improved, including disability, quality of life, sleep, and fatigue. In addition, VRNT was associated with modest increases in functional connectivity of the somatomotor and default mode networks and decreased white matter fractional anisotropy in the corpus callosum adjacent to anterior cingula, relative to the control condition. This, VRNT showed preliminary efficacy in significantly reducing pain and improving overall functioning, possibly via changes in somatosensory and prefrontal brain networks.
Optimisation of TP53 reporters by systematic dissection of synthetic TP53 response elements
Authors: Trauernicht Max , Rastogi Chaitanya , Manzo Stefano G. , Bussemaker Harmen J. , van Steensel Bas
Published: July 2023

TP53 is a transcription factor that controls multiple cellular processes, including cell cycle arrest, DNA repair, and apoptosis. The relation between TP53 binding site architecture and transcriptional output is still not fully understood. Here, we systematically examined in three different cell lines the effects of binding site affinity and copy number on TP53-dependent transcriptional output, and also probed the impact of spacer length and sequence between adjacent binding sites, and of core promoter identity. Paradoxically, we found that high-affinity TP53 binding sites are less potent than medium-affinity sites. TP53 achieves supra-additive transcriptional activation through optimally spaced adjacent binding sites, suggesting a cooperative mechanism. Optimally spaced adjacent binding sites have a ∼10-bp periodicity, suggesting a role for spatial orientation along the DNA double helix. We leveraged these insights to construct a log-linear model that explains activity from sequence features, and to identify new highly active and sensitive TP53 reporters.
Fecal Dysbiosis and Inflammation in Intestinal-Specific Cftr Knockout Mice on Regimens Preventing Intestinal Obstruction
Authors: Young Sarah M. , Woode Rowena A. , Williams Estela , Ericsson Aaron , Clarke Lane L.
Published: July 2023

Chronic intestinal inflammation is a poorly understood manifestation of Cystic Fibrosis (CF), which may be refractory to ion channel CFTR modulator therapy. People with CF exhibit intestinal dysbiosis which has potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia and in the leukocyte population. Here, we investigate the contribution of intestinal epithelial-specific loss of Cftr (iCftr KO) to dysbiosis and inflammation in mice treated with either of two anti-obstructive dietary regimens necessary to maintain CF mouse models (PEG laxative or a liquid diet, LiqD). Feces collected from iCftr KO mice and their wildtype (WT) sex-matched littermates were used to measure fecal calprotectin and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT samples of mice consuming either PEG or LiqD. PEG iCftr KO mice did not show a change in α-diversity versus WT but demonstrated a significant difference in microbial composition (β-diversity) with increases in phylumProteobacteria, familyPeptostreptococcaceae, four genera ofClostridiaincludingC. innocuum, and mucolytic genusAkkermansia. Fecal microbiome analysis of LiqD iCftr KO mice showed both decreased α-diversity and differences in microbial composition with increases inProteobacteriafamilyEnterobacteriaceae,FirmicutesfamiliesClostridiaceaeandPeptostreptococcaceae, and enrichment ofClostridium perfringens,C. innocuum,C. difficile, mucolyticRuminococcus gnavus, and reduction ofAkkermansia. It was concluded that epithelial-specific loss of Cftr is a major driver of CF intestinal dysbiosis and inflammation with significant similarities to previous studies of global Cftr KO mice.

New and noteworthy

Chronic intestinal inflammation is a manifestation of cystic fibrosis (CF), a disease caused by loss of the anion channel CFTR that is expressed in many tissues. This study shows that intestinal epithelial cell-specific loss of CFTR (iCftr KO) in mice is sufficient to induce intestinal dysbiosis and inflammation. Studies were performed on mice consuming either dietary regimen (PEG laxative or liquid diet) routinely used to prevent obstruction in CF mice.
The influence of HLA genetic variation on plasma protein expression
Authors: Krishna Chirag , Chiou Joshua , Lee Isac , Kim Hye In , Aksit Melis Atalar , Sakaue Saori , Schack David Von , Raychaudhuri Soumya , Ziemek Daniel , Hu Xinli
Published: July 2023

Polymorphism in the human leukocyte antigen class I (HLA-I) and class II (HLA-II) genes is strongly implicated in susceptibility to immune-mediated diseases. However, the molecular effects of HLA genetic variation, including and beyond antigen presentation, remain unclear. Here we examined the effect of HLA genetic variation on the expression of 2940 plasma proteins using imputed HLA variants in 45,330 Europeans in the UK Biobank. We detected 504 proteins (17.1% of all proteins tested) affected by HLA genetic variation (HLA-pQTL), including widespreadtransregulation of protein expression by autoimmune disease risk alleles. HLA-pQTL were enriched in gene families related to antigen presentation (e.g. B2M), T cell fate (CD8A; CD4), chemokines (CCL19; CCL21), and NK and macrophage receptors (KIR; LILRA/B), suggesting that HLA polymorphism affects both adaptive and innate immunity. HLA-pQTL also affected expression of diverse proteins with unclear roles in the immune response (e.g. SFTPD, LRPAP1, ENPP6, NPTX1), as well as drug targets for immune-mediated diseases, suggesting complex regulatory roles of the HLA loci. AmongtransHLA-pQTL, HLA variants explained 0.1-42.9% of the protein expression variance. Fine-mapping revealed that most HLA-pQTL implicated amino acid positions within the peptide binding groove, suggesting thattransregulation of plasma protein expression by the HLA loci is primarily a consequence of antigen presentation. We also show that HLA-I and II uniquely affect different proteins and biological mechanisms. Altogether, our data reveal the effects of HLA genetic variation on protein expression and aid the interpretation of associations between HLA alleles and immune-mediated diseases.
Identifying novel links between cardiovascular disease and insomnia by Drosophila modeling of genes from a pleiotropic GWAS locus
Authors: Abou Daya Farah , Mandigo Torrey , Ober Lily , Patel Dev , Maher Matthew , Math Suraj , Tchio Cynthia , Walker James A. , Saxena Richa , Melkani Girish C.
Published: July 2023

Insomnia symptoms have been associated with cardiovascular disease (CVD), doubling the risk of incident CVD, but specific shared pathways remain poorly understood. Recently, genome-wide association studies (GWAS) identified genetic loci significantly associated with insomnia symptoms, including one locus (near ATP5G1, UBE2Z, SNF8, IGF2BP1, and GIP) that was previously linked with CVD in an independent GWAS. To evaluate the cell-autonomous role of genes within the 17q21 insomnia and CVD locus, we used Drosophila melanogaster models to perform tissue-specific RNAi knockdown of four conserved orthologues (ATPSynC, Lsn, Bruce, and Imp) in neurons and in the heart. To identify non-cell-autonomous mechanisms, we also assessed heart function in flies with neuronal-specific knockdown and sleep in flies with heart-specific knockdown. Neuronal and cardiac-specific RNAi knockdown of several of the genes conserved in Drosophila led to compromised sleep quality and impaired cardiac performance. Neuronal-specific knockdown of ATPSynC, Imp, and Lsn led to disruptions in sleep quantity and quality. Knockdown of ATPSynC and Lsn in the heart led to significantly reduced cardiac performance without and with cardiac dilation, respectively. Furthermore, Lsn and ATPSynC-suppressed hearts showed disruption in the actin-containing myofibrillar organization and led to a significantly shortened lifespan. Non-cell-autonomous effects were seen both from neurons to heart (Imp), and heart to neurons (ATPSynC and Lsn). Specifically, Imp neuronal knockdown led to a significantly compromised cardiac function, whereas knockdown of ATPSynC and Lsn in the heart led to compromised sleep characterized by increased sleep fragmentation, both accompanied by an increase in inflammation through Upd3, an inflammatory cytokine, in the heart or head, respectively. We also demonstrate disrupted cardiac function or sleep upon cardiac-specific or neuronal-specific overexpression of Upd3, respectively, showing a direct link between cardiac dysfunction and sleep disruption through inflammation. Our study reveals tissue-specific and cross-tissue consequences of Drosophila knockdown of multiple genes at this locus, providing novel insights into potential genetic mechanisms linking CVD and insomnia. Our study also highlights the key role of these four conserved genes in both sleep and cardiac function.
Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer’s disease and progressive supranuclear palsy
Authors: Batra Richa , Krumsiek Jan , Wang Xue , Allen Mariet , Blach Colette , Kastenmüller Gabi , Arnold Matthias , Ertekin-Taner Nilüfer , Kaddurah-Daouk Rima F. ,   Alzheimer’s Disease Metabolomics Consortium (ADMC)
Published: July 2023

Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP). While metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed. We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies. Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B. Taken together, our findings underscore vast alterations in the brain’s metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP.
Fight or Flight: Emergency Healthcare Workers’ Willingness to Work during Crises and Disasters: A cross-sectional multicentre study in the Netherlands
Authors: Engels Lindsy M.J. , Barten Dennis G. , Boumans Thimo J.T. , Gaakeer Menno I. , Latten Gideon H.P. , Mehagnoul Jannet , Tapirdamaz Özlem , van Osch Frits , Mortelmans Luc
Published: July 2023

Objective

Expanding staff levels is a strategy for hospitals to increase surge capacity. This study aimed to evaluate whether emergency healthcare workers (HCWs) are willing to work (WTW) during a crises or disaster and which working conditions would influence their decision.

Methods

HCWs of emergency departments (ED) and intensive care units (ICU) of five Dutch hospitals were surveyed about elevens disaster scenarios. For each scenario, HCWs were asked about their WTW and which conditions would influence their decision. Knowledge and perceived risk and danger was assessed per scenario.

Results

306/630 HCWs completed the survey. An influenza epidemic, SARS-CoV-2 pandemic and natural disaster were associated with highest WTW rates (69.0%, 63.7% and 53.3% respectively). WTW was lowest in nuclear incident (4.6%) and dirty bomb (3.3%) scenarios. WTW was higher in physicians than in nurses. Male ED HCWS, single HCWs and childless HCWs were more often WTW. Personal protective equipment (PPE) and safety of HCWs’ family were the most important working conditions. Perceived knowledge scored lowest in dirty bomb, biological and nuclear incident scenarios. These scenarios rated highest with regards to perceived danger.

Conclusions

WTW depended on disaster type, profession and working department. Provision of PPE and safety of HCWs’ family were found to be predominant working conditions.
The Cost of Keeping Patients Waiting: Retrospective Treatment-Control Study of Additional Healthcare Utilisation for UK Patients Awaiting Elective Treatment Following COVID-19
Authors: James Charlotte , Denholm Rachel , Wood Richard
Published: July 2023

Objective

The COVID-19 pandemic has led to increased waiting times for elective treatments in many countries. This study seeks to address a deficit in the literature concerning the effect of long waits on the wider consumption of healthcare resources.

Methods

We carried out a retrospective treatment-control study in a healthcare system in South West England from 15 June 2021 to 15 December 2021. We compared weekly contacts with health services of patients waiting over 18 weeks for treatment (‘Treatments’) and people not on a waiting list (‘Controls’). Controls were matched to Treatments based on age, sex, deprivation and multimorbidity. Treatments were stratified by the clinical specialty of the awaited treatment, with healthcare usage assessed over various healthcare settings. T-tests assessed whether there was an increase in healthcare utilisation and bootstrap resampling was used to estimate the magnitude of any differences.

Results

A total of 44,616 patients were waiting over 18 weeks (the constitutional target in England) for treatment during the study period. Evidence suggests increases (p < 0.05) in healthcare utilisation for all specialties. Patients in the Cardiothoracic Surgery specialty had the largest increase, requiring 17.9 [4.3, 33.8] additional contacts with secondary care and 17.3 [-1.1, 34.1] additional prescriptions per year.

Conclusion

People waiting for treatment consume higher levels of healthcare than comparable individuals not on a waiting list. These findings are relevant for clinicians and managers in better understanding patient need and reducing harm. Results also highlight the possible ‘false economy’ in failing to promptly resolve long elective waits.

Highlights

Long waits for elective care can result in additional healthcare needs to manage symptoms up to the point of definitive treatment. While previous studies indicate some association, these mainly consider only a single elective specialty and are limited in the range of healthcare settings covered.

The large number of long-wait pathways produced as a consequence of COVID-19 disruption allows for a more holistic analysis, covering the full range of elective treatment specialties and wider healthcare impacts across primary, secondary, mental health, and community care, as well as emergency service calls and prescriptions.

Analysis of 44,616 elective care pathways reveals evidence of increases in wider healthcare consumption additional to that expected for similar patients not awaiting elective treatment. This suggests a ‘false economy’ in failing to promptly resolve elective pathways, which should be reflected by healthcare providers in long-term resource allocation decisions.
Sources of prey availability data alter interpretation of outputs from prey choice null networks
Authors: Cuff Jordan P. , Tercel Maximillian P.T.G. , Windsor Fredric M. , Hawthorne Ben S.J. , Hambäck Peter A. , Bell James R. , Symondson William O.C. , Vaughan Ian P.
Published: July 2023

Null models provide an invaluable baseline against which to test fundamental ecological hypotheses and highlight patterns in foraging choices that cannot be explained by neutral processes or sampling artefacts. In this way, null models can advance our understanding beyond simplistic dietary descriptions to identify drivers of interactions. This method, however, requires estimates of resource availability, which are generally imperfect representations of highly dynamic systems. Optimising method selection is crucial for study design, but the precise effects of different resource availability data on the efficacy of null models are poorly understood.

Using spider-prey networks as a model, we used prey abundance (suction sample) and activity density (sticky trap) data, and combinations of the two, to simulate null networks. We compared null diet composition, network properties (e.g., connectance and nestedness) and deviations of simulations from metabarcoding-based spider dietary data (to ascertain how different prey availability data alter ecological interpretation.

Different sampling methods produced different null networks and inferred distinct prey selectivity. Null networks based on prey abundance and combined frequency-of-occurrence data more closely resembled the observed diet composition, and those based on prey abundance, activity density and proportionally combined data generated network properties most like dietary metabarcoding networks.

We show that survey method choice impacts all aspects of null network analyses, the precise effects varying between methods but ultimately altering ecological interpretation by increasing disparity in network properties or trophic niches between null and directly constructed networks. Merging datasets can generate more complete prey availability data but is not a panacea because it introduces different biases. The choice of method should reflect the research hypotheses and study system being investigated. Ultimately, survey methods should emulate the foraging mode of the focal predator as closely as possible, informed by the known ecology, natural history and behaviour of the predator.
A genomic exploration of the possible de-extirpation of the Zanzibar leopard
Authors: Sun Xin , Cavill Emily Louisa , Margaryan Ashot , Lin Jianqing , Thingaard Søren , Said Tamrini A. , Gopalakrishnan Shyam , Gilbert M. Thomas P.
Published: July 2023

The recently extirpated Zanzibar leopard was the only known African leopard (Panthera pardus spp.) population restricted exclusively to a major island habitat. Although its demise was driven through habitat change and conflict with humans, given its role as a keystone species for the Zanzibar Archipelago, its potential reintroduction might offer a means for helping preserve the natural biodiversity of its former habitat. Whether this is feasible, however, would be contingent on both whether closely related source populations can be identified on mainland Africa, and whether the Zanzibar form exhibited any special adaptations that might need to be considered when choosing such a source. In light of these questions, we genomically profiled two of the six known historic specimens, to explore whether they represent a realistic candidate for de-extirpation through reintroduction. Our analyses indicate that despite its geographic separation, the Zanzibar leopard shared a close genetic relationship with mainland East African individuals. Furthermore, although its uniqueness as an island population was emphasised by genomic signatures of high inbreeding and increased mutation load, the latter similar to the level of the critically endangered Amur leopard (P. p. orientalis), we find no evidence of positive selection unique to Zanzibar. We therefore conclude that should attempts to restore leopards to Zanzibar be planned, then mainland East African leopards would provide a suitable gene pool, whether using genetic engineering or conventional rewilding approaches.
Massively Concurrent Sub-Cellular Traction Force Videography enabled by Single-Pixel Optical Tracers (SPOTs)
Authors: Marvin Tan Xing Haw , Wang Yijie , Zhu Xiongfeng , Mendes Felipe Nanni , Chung Pei-Shan , Chow Yu Ting , Man Tianxing , Lan Hsin , Lin Yen-Ju , Zhang Xiang , Zhang Xiaohe , Nguyen Thang , Ardehali Reza , Teitell Michael A. , Deb Arjun , Chiou Pei-Yu
Published: July 2023

We report a large field-of-view and high-speed videography platform for measuring the sub-cellular traction forces of more than 10,000 biological cells over 13mm2at 83 frames per second. Our Single-Pixel Optical Tracers (SPOT) tool uses 2-dimensional diffraction gratings embedded into a soft substrate to convert cells’ mechanical traction stress into optical colors detectable by a video camera. The platform measures the sub-cellular traction forces of diverse cell types, including tightly connected tissue sheets and near isolated cells. We used this platform to explore the mechanical wave propagation in a tightly connected sheet of Neonatal Rat Ventricular Myocytes (NRVMs) and discovered that the activation time of some tissue regions are heterogeneous from the overall spiral wave behavior of the cardiac wave.

One-Sentence Summary

An optical platform for fast, concurrent measurements of cell mechanics at 83 frames per second, over a large area of 13mm2.