bluuebunny/crossref_metadata_2025 huggingface dataset:
To leave no one behind: Assessing utilization of maternal newborn and child health services by all the 13 particularly vulnerable tribal groups (PVTGs) of Odisha, India
Authors: Ghosal Jyoti , Bal Madhusmita , Das Arundhuti , Panda Bhuputra , Ranjit‬ Manoranjan , Behera Manas Ranjan , Kar Sonali , Satpathy Sudhir Kumar , Dutta Ambarish , Pati Sanghamitra
Published: January 2024

Background

Indigenous tribal people experience lower coverage of maternal, newborn and child healthcare (MNCH) services worldwide, including in India. Meanwhile, Indian tribal people comprise a special sub-population who are even more isolated, marginalized and underserved, designated as particularly vulnerable tribal groups (PVTGs). However, there is an extreme paucity of evidence on how this most vulnerable sub-population utilizes health services. Therefore, we aimed to estimate MNCH service utilization by all the 13 PVTGs of the eastern Indian state of Odisha and compare that with state and national rates.

Methods

A total of 1186 eligible mothers who gave birth to a live child in last 5 years, were interviewed using a validated questionnaire. The weighted MNCH service utilization rates were estimated for antenatal care (ANC), intranatal care (INC), postnatal care (PNC) and immunization (for 12–23-month-old children). The same rates were estimated for state (n = 7144) and nationally representative samples (n = 176 843) from National Family Health Survey-5.

Results

The ANC service utilization among PVTGs were considerably higher than national average except for early pregnancy registration (PVTGs 67% versus national 79.9%), and 5 ANC components (80.8% versus 82.3%). However, their institutional delivery rates (77.9%) were lower than averages for Odisha (93.1%) and India (90.1%). The PNC and immunization rates were substantially higher than the national averages. Furthermore, the main reasons behind greater home delivery in the PVTGs were accessibility issues (29.9%) and cultural barriers (23.1%).

Conclusion

Ours was the first study of MNCH service utilization by PVTGs of an Indian state. It is very pleasantly surprising to note that the most vulnerable subpopulation of India, the PVTGs, have achieved comparable or often greater utilization rates than the national average, which may be attributable to overall significantly better performance by the Odisha state. However, PVTGs have underperformed in terms of timely pregnancy registration and institutional delivery, which should be urgently addressed.
Report and literature review of four cases of EWSR1::NFATC2 round cell sarcoma
Authors: Liu Lili , Li Lan , Ding Yi , Kong Fangzhou , Mo Wenfa , Ye Hongtao , Shen Danhua
Published: January 2024

Background

EWSR1::NFATC2 rearranged sarcomas are a group of rare round, undifferentiated sarcomas with clinicopathological features different from those of Ewing's sarcoma (ES) family and other non-ES sarcomas. We report 4 cases of this rare sarcoma and review their features.

Materials and methods

Four cases of EWSR1::NFATC2 rearranged round cell sarcoma of the bone from the Pathology Department of Peking University People's Hospital were retrospectively studied. Clinical and pathological data were summarized, and immunohistochemical staining, fluorescence in situ hybridization (FISH), and Next-generation sequencing (NGS) were performed. Relevant literature reports were also reviewed.

Results

Among the four cases of EWSR1::NFATC2 rearranged round cell sarcoma, three were male, and one was female, with the age ranged from 14 to 34 years old at diagnosis (mean age: 27.5 years). All tumors were located in the femur and ranged in size from 4 to 8cm (mean 6cm), involving the surrounding soft tissues. All four patients underwent surgical treatment, and three received chemotherapy and radiotherapy postoperatively. Follow-up results showed that all four patients were alive. Histologically, the tumors exhibited small round cell sarcoma phenotype, with the stroma rich in mucin or exhibiting a glassy appearance. The tumor cells diffusely expressed CD99, NKX2.2, NKX3.1 and focal expression of CK and EMA was observed. FISH analysis showed that EWSR1 gene rearrangement was detected in all 4 cases, accompanied by 5' locus amplification. EWSR1::NFATC2 fusion probe demonstrated multi yellow fusion signals. NGS identified EWSR1::NFATC2 breakpoints in exon 9 and exon 3 in all 4 cases. The average follow-up duration of the study group was 88 months (range from 26—180 months). One case experienced both local recurrence and metastasis to the lung and chest wall. One case presented with local recurrence. The remaining two cases did not have the recurrence or metastasis.

Conclusion

Although the disease can locally recur and metastasize to the lungs, its mortality rate is significantly lower than that of Ewing sarcoma and other high-grade small round cell undifferentiated sarcomas. Therefore, it supports to classify this tumor as a separate subtype of small round cell sarcoma.
Percutaneous monoplanar screws versus hybrid fixed axial and polyaxial screws in intermediate screw fixation for traumatic thoracolumbar burst fractures: a case–control study
Authors: Han Yaozheng , Ma Jun , Zhang Guoquan , Huang Liangliang , Kang Hui
Published: January 2024

Background

To compare the clinical and radiological outcomes of monoplanar screws (MSs) versus hybrid fixed axial and polyaxial screws (HSs) in percutaneous short-segment intermediate screw fixation (PSISF) for traumatic thoracolumbar burst fractures (TTBFs) in patients without neurologic impairment.

Methods

A consecutive series of 100 patients with single-segment TTBFs and no neurologic impairment who underwent PSISF with 6 monoplanar screws (MS group) or correct were retrospectively enrolled. The demographic data, radiologic evaluation indicators, perioperative indicators and clinical assessment indicators were analysed between the MS group and HS group.

Results

The demographic data and perioperative indicators were not significantly different in the two groups (P > 0.05). The postoperative anterior vertebral height ratio (AVHR), kyphosis Cobb angle (KCA), vertebral wedge angle (VWA) and spinal canal encroachment rate (SCER) were significantly improved in both groups (*P < 0.05). The MS group obtained better correction than the HS group in terms of improvement in the AVHR, KCA and VWA after surgery (*P < 0.05). At the last follow-up, the MS group had less correction loss of AVHR, KCA and VWA (*P < 0.05). The MS group presented greater improvement in the SCER at the last follow-up (*P < 0.05). The visual analogue scale (VAS) score and Oswestry Disability Index (ODI) score of all patients were significantly better postoperatively than those preoperatively (*P < 0.05), and the scores collected at each follow-up visit did not differ significantly between the two groups (P > 0.05). In the MS group, no internal fixation failure was observed during the follow-up period, but, in the HS group, two cases of internal fixation failure were observed at the last follow-up (one case of rod loosening and one case of screw breakage).

Conclusions

Both MSs and HSs fixation are effective treatments for TTBFs and have comparable clinical outcomes. In contrast, MSs fixation can improve the correction effect, better improve the SCER, and further reduce correction loss as well as reduce the incidence of instrumentation failure. Therefore, MSs fixation might be a better option for treating TTBFs in patients without neurological deficits.
Strategy for acute DeBakey type I aortic dissection considering midterm results: a retrospective cohort study comparing ascending aortic replacement and total arch replacement with frozen elephant trunk technique
Authors: Takagi Sho , Goto Yoshihiro , Yanagisawa Junji , Ogihara Yui , Okawa Yasuhide
Published: January 2024

Background

Acute type A aortic dissection is treated with an emergency procedure that uses ascending aortic replacement (AAR). However, to avoid a residual dissected aorta with a false lumen, total arch replacement (TAR) is required. The frozen elephant trunk (FET) technique is a promising surgical approach that promotes false lumen obliteration in a single step. Therefore, this retrospective single-center study aimed to evaluate the operative outcomes of AAR and TAR with FET.

Methods

Between 2007 and 2021, 143 patients with acute DeBakey type I aortic dissection underwent a central repair using AAR (n = 95) or TAR with FET (n = 43). All perioperative variables, the duration of all-cause mortality, and aortic events defined as dilatation of the distal aorta > 5 cm, new occurrences of aortic dissection, distal aortic surgery, and distal aortic rupture were recorded. We compared these perioperative variables and mid-term results with an additional focus on distal aortic events.

Results

Patient background data did not differ between the two groups. Perioperative results for the TAR with FET group vs the AAR group showed similar operative times (306 vs 298 min, P = 0.862), but the TAR group had longer cardiopulmonary bypass times (154 vs 179 min, P < 0.001). The freedom from all-cause death for the TAR vs AAR groups using the Kaplan–Meier method was 81.9% vs 85.4% and 78.0% vs 85.4% (P = 0.407) at 1 and 3 years, respectively. Freedom from aorta-related events was 90.6% vs 97.6% and 69.3% vs 87.0% (P = 0.034) at 1 and 3 years, respectively.

Conclusions

TAR with FET had comparable perioperative results to AAR in acute DeBakey type I aortic dissection and was considered a valuable method to avoid aorta-related events in the midterm.
Developing a community-led rare disease ELSI research agenda
Authors: Berrios Courtney , McBeth Macy , Bradley-Ewing Andrea , Schuetz Nikolaus , Campbell Annette , Talebizadeh Zohreh , Garrett Jeremy R. , Falicov Tamara , Martinez Francisco ,   Rare Voices Advisory Group, Adams Jensen , Akpan Jewel , Baesel-Freund Kelly L. , Biyala Urvi , Cramer Emily , Freeman Kimberly , Gallagher Terrence , Jarrar Ada , Jones Linda Vaughn , Lewis Tamorah , Long George , Petersen Nancy , Prout Kerry K. , Rosas Alejandro , Strenk Meghan , Wirtz Melissa , Wright S. Margaret , Wood Miller , Wood West , Hurley Emily A.
Published: January 2024

Background

Research priorities are best defined through engagement with communities who will be impacted by the research and have lived experience of the topics to be studied. We aimed to establish a pediatric rare disease community stakeholder group and empower them in (1) eliciting perspectives from affected families in the wider region and (2) synthesizing collective ideas into a research agenda focused on shared ethical, legal, and social implications (ELSI) across rare disease.

Methods

This two-year project utilized a community-centered approach to engage rare disease community members as equal partners in developing a research agenda for ELSI in rare disease. We established “Rare Voices” (RV), a 22-member stakeholder group of patients, parents, clinicians and researchers. Following capacity-building trainings, RV designed and conducted listening sessions with teen patients and parents of children with rare diseases to explore challenges, positive experiences, and ethical concerns. Listening session findings were synthesized and contextualized into research topics, which RV members further refined and prioritized. We used established measures to assess RV member engagement and satisfaction.

Results

From 14 listening sessions with parents (n = 52) and teen patients (n = 13), RV identified eight core research topics as most important for future rare disease research: coordinating care, communication, accessing resources and care, impact on family unit, community and support in society, mental health and identity, ethical aspects of care, and uncertainty. RV members were highly engaged throughout the two-year project and reported high levels of satisfaction with the experience and research agenda.

Conclusions

Through capacity-building and authentic engagement, this project resulted in a community-led rare disease research agenda to guide future rare disease ELSI research that aligns with patients’ and families’ priorities. An environment of equal partnership and respect created a space for mutual learning where community members were empowered to shape the research agenda based on their collective experiences. The agenda recognizes the shared psychosocial and healthcare experiences of rare disease and offers practical areas of research to address patient and family needs.
Safety and efficacy of ketorolac continuous infusion for multimodal analgesia of vaso-occlusive crisis in patients with sickle cell disease
Authors: Pinto Valeria Maria , Gianesin Barbara , Sardo Salvatore , Mazzi Filippo , Baiardi Giammarco , Menotti Sofia , Piras Fabio , Quintino Sabrina , Robello Giacomo , Mattioli Francesca , Finco Gabriele , Forni Gian Luca , De Franceschi Lucia
Published: January 2024

Pain is an hallmark of sickle-cell-related acute clinical manifestations as part of acute vaso-occlusive crisis (VOC). In SCD pain has different origins such as vascular or neuropathic pain, which requires multimodal analgesia. This is based on the administration of drugs with different pharmacological mechanisms of action, maximizing analgesia and minimizing their adverse events and the risk of drug-addition in patients experiencing acute-recurrent pain events as in SCD. Ketorolac is a potent non-narcotic analgesic, being relatively safe and effective during pain-management in children and adults. Up to now, there is a lack of safety information on continuous infusion ketorolac as used to control acute pain in patients with SCD, and the benefits/risks ratio needs to be investigated. Here, we report for the first time the safety profile of ketorolac in the special population of patients with SCD. We confirmed that ketorolac in combination with tramadol, an opioid like molecule, is effective in pain control of adult patients with SCD experiencing acute severe VOCs defined by pain visual analog scale. Our study shows that short term (72 h) continuous infusion of ketorolac plus tramadol is not associated with adverse events such as liver or kidney acute disfunction or abnormalities in coagulation parameters during patients’ hospitalization and within 30 days after patients discharge. This is extremely important for patients with SCD, who should have access to multimodal therapy to control recurrent acute pain crisis in order to limit central sensitization a fearsome issue of undertreated recurrent acute pain and of chronic pain.
Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD
Authors: Khalil Bilal , Linsenmeier Miriam , Smith Courtney L. , Shorter James , Rossoll Wilfried
Published: January 2024

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.

Graphical Abstract
Vascular access challenges in hemodialysis children
Authors: Salah Doaa M. , Fadel Fatina I. , Abdel Mawla Mohamed A. , Mooty Hesham NAbdel , Ghobashy Mohamed El , Salem Amr M. , Fathallah Mohamed Gamal , Abd Alazem Eman Abobakr
Published: January 2024

Background

Hemodialysis (HD) success is dependent mainly on vascular access (VA). The aim of this study is to share the experience of Pediatric Nephrology Unit (PNU), Cairo University Children’s Hospital (CUCH), with VA-related obstacles in end stage kidney disease (ESKD) HD children.

Methods

This is a retrospective analysis of VA related data of 187 ESKD children received regular HD over 3 year duration (2019–2021). Kaplan–Meier curves were used to present arteriovenous fistula (AVF) and cuffed catheters survivals.

Results

Uncuffed central venous catheter (CVC) was the primary VA for HD in up to 97.3% with 2.7% of patients had AVF performed and attained maturation before initiation of regular HD. Fifty-six (29.9%) patients have inserted 120 tunneled CVCs. AVFs & AV grafts (AVF) were performed in 79 (42.2%) and 6 (3.2%) patients respectively. There were 112 uncuffed CVCs implanted beneath the screen in Rt internal jugular vein (IJV) (44%) Lt IJV (17%), right internal mammary vein (2.7%) while Trans hepatic (TH) technique was used to place 39 uncuffed CVCs (34%) in the inferior vena cava (IVC). Catheter-related bacteremia (CRB) was the most frequent complication in uncuffed and cuffed CVCs (2.58 / 100 catheters day and 10.1 /1000 catheter days respectively). AVFs achieved a high success rate (83%) after 757.71 ± 512.3 functioning days.

Conclusion

Native AVF is the preferred VA for pediatric HD but its creation is limited by the small sized vessels where non-cuffed CVC could be a reasonable relatively long-term alternative. Challenging situations (occluded central veins) could benefit from TH technique of CVC insertion in IVC.
Increased risk of contralateral breast cancer for BRCA1/2 wild-type, high-risk Korean breast cancer patients: a retrospective cohort study
Authors: Kang Eunhye , Jung Ji-Jung , Lim Changjin , Kim Hong-Kyu , Lee Han-Byoel , Han Wonshik , Moon Hyeong-Gon
Published: January 2024

Background

This study aimed to investigate the contralateral breast cancer (CBC) recurrence rate in Korean breast cancer patients according to their BRCA1/2 germline mutation status, focusing particularly on the CBC recurrence risk in BRCA1/2 negative (BRCAx) patients.

Methods

We conducted a retrospective study on 13,107 primary breast cancer patients. The patients were divided into high-risk and low-risk groups for hereditary breast cancer based on the Korean National Health Insurance Service’s eligibility criteria for BRCA1/2 germline mutation testing. The high-risk group was further categorized into the BRCAmutation group, the BRCAxgroup, and the not tested group. We evaluated the overall survival and cumulative risk of developing CBC in these patients.

Results

Among 4494 high-risk patients, 973 (21.7%) underwent genetic testing for BRCA1/2 germline mutation, revealing mutations in 158 patients (16.2%). We observed significant overall survival differences across all four groups, with the high-risk, not-tested group demonstrating notably worse overall survival (p < 0.001). However, when adjusted for other prognostic factors, there was no significant differences in hazard ratio of death between the four groups. The cumulative risk of CBC also varied among the groups. Patients with BRCA1/2 mutations showed a 7.3-fold increased risk of CBC compared to the low-risk group (95% CI 4.11–13.0, p < 0.001). Interestingly, BRCAx patients also demonstrated a significantly higher risk of CBC (HR 2.77, 95% CI 1.76–4.35, p < 0.001). The prognostic importance of the BRCAx for CBC recurrence persisted after adjusting for the age and subtype, but became insignificant when the family history of breast cancer was adjusted.

Conclusion

Breast cancer patients who are at high risk of hereditary breast cancer but with wild-type BRCA 1/2 genes (BRCAx) have increased risk of developing contralateral breast cancer when compared to the low-risk patients. More careful surveillance and follow-up can be offered to these patients especially when they have family history of breast cancer.
SURGE: uncovering context-specific genetic-regulation of gene expression from single-cell RNA sequencing using latent-factor models
Authors: Strober Benjamin J. , Tayeb Karl , Popp Joshua , Qi Guanghao , Gordon M. Grace , Perez Richard , Ye Chun Jimmie , Battle Alexis
Published: January 2024

Genetic regulation of gene expression is a complex process, with genetic effects known to vary across cellular contexts such as cell types and environmental conditions. We developed SURGE, a method for unsupervised discovery of context-specific expression quantitative trait loci (eQTLs) from single-cell transcriptomic data. This allows discovery of the contexts or cell types modulating genetic regulation without prior knowledge. Applied to peripheral blood single-cell eQTL data, SURGE contexts capture continuous representations of distinct cell types and groupings of biologically related cell types. We demonstrate the disease-relevance of SURGE context-specific eQTLs using colocalization analysis and stratified LD-score regression.
Structural variation and DNA methylation shape the centromere-proximal meiotic crossover landscape in Arabidopsis
Authors: Fernandes Joiselle B. , Naish Matthew , Lian Qichao , Burns Robin , Tock Andrew J. , Rabanal Fernando A. , Wlodzimierz Piotr , Habring Anette , Nicholas Robert E. , Weigel Detlef , Mercier Raphael , Henderson Ian R.
Published: January 2024

Background

Centromeres load kinetochore complexes onto chromosomes, which mediate spindle attachment and allow segregation during cell division. Although centromeres perform a conserved cellular function, their underlying DNA sequences are highly divergent within and between species. Despite variability in DNA sequence, centromeres are also universally suppressed for meiotic crossover recombination, across eukaryotes. However, the genetic and epigenetic factors responsible for suppression of centromeric crossovers remain to be completely defined.

Results

To explore the centromere-proximal meiotic recombination landscape, we map 14,397 crossovers against fully assembled Arabidopsis thaliana (A. thaliana) genomes. A. thaliana centromeres comprise megabase satellite repeat arrays that load nucleosomes containing the CENH3 histone variant. Each chromosome contains a structurally polymorphic region of ~3–4 megabases, which lack crossovers and include the satellite arrays. This polymorphic region is flanked by ~1–2 megabase low-recombination zones. These recombination-suppressed regions are enriched for Gypsy/Ty3 retrotransposons, and additionally contain expressed genes with high genetic diversity that initiate meiotic recombination, yet do not crossover. We map crossovers at high-resolution in proximity to CEN3, which resolves punctate centromere-proximal hotspots that overlap gene islands embedded in heterochromatin. Centromeres are densely DNA methylated and the recombination landscape is remodelled in DNA methylation mutants. We observe that the centromeric low-recombining zones decrease and increase crossovers in CG (met1) and non-CG (cmt3) mutants, respectively, whereas the core non-recombining zones remain suppressed.

Conclusion

Our work relates the genetic and epigenetic organization of A. thaliana centromeres and flanking pericentromeric heterochromatin to the zones of crossover suppression that surround the CENH3-occupied satellite repeat arrays.
Thoracic paravertebral block for perioperative lung preservation during VATS pulmonary surgery: study protocol of a randomized clinical trial
Authors: Zhu Jiayu , Wei Biyu , Wu Lili , Li He , Zhang Yi , Lu Jinfeng , Su Shaofei , Xi Chunhua , Liu Wei , Wang Guyan
Published: January 2024

Background

Postoperative pulmonary complications (PPCs) extend the length of stay of patients and increase the perioperative mortality rate after video-assisted thoracoscopic (VATS) pulmonary surgery. Thoracic paravertebral block (TPVB) provides effective analgesia after VATS surgery; however, little is known about the effect of TPVB on the incidence of PPCs. The aim of this study is to determine whether TPVB combined with GA causes fewer PPCs and provides better perioperative lung protection in patients undergoing VATS pulmonary surgery than simple general anaesthesia.

Methods

A total of 302 patients undergoing VATS pulmonary surgery will be randomly divided into two groups: the paravertebral block group (PV group) and the control group (C group). Patients in the PV group will receive TPVB: 15 ml of 0.5% ropivacaine will be administered to the T4 and T7 thoracic paravertebral spaces before general anaesthesia induction. Patients in the C group will not undergo the intervention. Both groups of patients will be subjected to a protective ventilation strategy during the operation. Perioperative protective mechanical ventilation and standard fluid management will be applied in both groups. Patient-controlled intravenous analgesia is used for postoperative analgesia. The primary endpoint is a composite outcome of PPCs within 7 days after surgery. Secondary endpoints include blood gas analysis, postoperative lung ultrasound score, NRS score, QoR-15 score, hospitalization-related indicators and long-term prognosis indicators.

Discussion

This study will better evaluate the impact of TPVB on the incidence of PPCs and the long-term prognosis in patients undergoing VATS lobectomy/segmentectomy. The results may provide clinical evidence for optimizing perioperative lung protection strategies.

Trial registration

ClinicalTrials.govNCT05922449. Registered on June 25, 2023.
Effect of maternal oxygen supplementation for parturient undergoing elective cesarean section by high-flow nasal oxygen compared with room air on fetal acidemia: study protocol for a randomized controlled trial
Authors: Li Yun-Hui , Lei Gui-Yu , Guo Jun , Yi Meng , Fu Yu-Jing , Wang Gu-Yan
Published: January 2024

Background

Maternal oxygen supplementation is usually used as an intrauterine resuscitation technique to prevent fetal hypoxia and acidemia during delivery. However, there has been a great deal of controversy regarding the effects of prophylactic maternal oxygen during cesarean section, during which the incidence of fetal acidemia seems to be higher compared with that during labor. High-flow nasal oxygen (HFNO) can improve oxygenation better in patients with high-flow oxygen airflow. The purpose of this study is to determine whether maternal oxygen supplementation with HFNO has a positive effect on fetal acidemia during cesarean section through umbilical arterial blood gas analysis.

Method

This prospective, single-center, randomized, double-blinded trial will enroll 120 patients undergoing cesarean section. Participants will be randomly assigned to the HFNO group or air group at a 1:1 ratio. For parturients in the HFNO group, the flow rate is 40L/min, and the oxygen is heated to 37℃ with humidity 100% oxygen concentration through the Optiflow high-flow nasal oxygen system. And for the air group, the flow rate is 2 L/min with an air pattern through the same device. The primary outcome was umbilical artery (UA) lactate. Secondary outcomes include UA pH, PO2, PCO2, BE, the incidence of pH < 7.20 and pH < 7.10, Apgar scores at 1 and 5 min, and neonatal adverse outcomes.

Discussion

Our study is the first trial investigating whether maternal oxygen supplementation with HFNO can reduce the umbilical artery lactate levels and the incidence of fetal acidemia in cesarean section under combined spinal-epidural anesthesia.

Trial registration

ClinicalTrials.gov NCT05921955. Registered on 27 June 2023.
Ultrahigh-throughput screening-assisted in vivo directed evolution for enzyme engineering
Authors: Chen Shuaili , Yang Zhanhao , Zhong Ze , Yu Shiqin , Zhou Jingwen , Li Jianghua , Du Guocheng , Zhang Guoqiang
Published: January 2024

Background

Classical directed evolution is a powerful approach for engineering biomolecules with improved or novel functions. However, it traditionally relies on labour- and time-intensive iterative cycles, due in part to the need for multiple molecular biology steps, including DNA transformation, and limited screening throughput.

Results

In this study, we present an ultrahigh throughput in vivo continuous directed evolution system with thermosensitive inducible tunability, which is based on error-prone DNA polymerase expression modulated by engineered thermal-responsive repressor cI857, and genomic MutS mutant with temperature-sensitive defect for fixation of mutations in Escherichia coli. We demonstrated the success of the in vivo evolution platform with β-lactamase as a model, with an approximately 600-fold increase in the targeted mutation rate. Furthermore, the platform was combined with ultrahigh-throughput screening methods and employed to evolve α-amylase and the resveratrol biosynthetic pathway. After iterative rounds of enrichment, a mutant with a 48.3% improvement in α-amylase activity was identified via microfluidic droplet screening. In addition, when coupled with an in vivo biosensor in the resveratrol biosynthetic pathway, a variant with 1.7-fold higher resveratrol production was selected by fluorescence-activated cell sorting.

Conclusions

In this study, thermal-responsive targeted mutagenesis coupled with ultrahigh-throughput screening was developed for the rapid evolution of enzymes and biosynthetic pathways.
Artemisinin-naphthoquine plus lower-dose primaquine to treat and prevent recurrence of Plasmodium vivax malaria: an open-label randomized and non-inferiority trial
Authors: Liu Hui , Xu Jian-Wei , Deng Dao-Wei , Yaw Bi , Nbwi Hkawn Shawng , Wei Chun , Zhou Xing-Wu , Li Jian-Xiong
Published: January 2024

Background

Plasmodium vivax malaria, with the widest geographic distribution, can cause severe disease and death. Primaquine is the main licensed antimalarial drug that can kill hypnozoites. The dose-dependent acute haemolysis in individuals with glucose-6-phospate dehydrogenase (G6PD) deficiency is the main safety concern when using primaquine. The recommended treatment regimen for P. vivax malaria is chloroquine plus primaquine for 14 days (CQPQ14) in Myanmar. The study aimed to evaluate the therapeutic efficacy, safety and adherence for the regimen of artemisinin-naphthoquine plus primaquine for 3 days (ANPQ3) in patients with P. vivax infections compared to those with CQPQ14.

Methods

The patients in the ANPQ3 group were given fixed-dose artemisinin-naphthoquine (a total 24.5 mg/kg bodyweight) plus a lower total primaquine dose (0.9 mg/kg bodyweight) for 3 days. The patients in the CQPQ14 group were given a total chloroquine dose of 30 mg/kg body weight for 3 days plus a total primaquine dose of 4.2 mg/kg bodyweight for 14 days. All patients were followed up for 365 days.

Results

A total of 288 patients completed follow-up, 172 in the ANPQ3 group and 116 in the CQPQ14 group. The first recurrence patients were detected by day 58 in both groups. By day 182, 16 recurrences had been recorded: 12 (7.0%) patients in the ANPQ3 group and 4 (3.4%) in the CQPQ14 group. The difference in recurrence-free patients was 3.5 (−8.6 to 1.5) percentage points between ANPQ3 and CQPQ14 group (P = 0.2946). By day 365, the percentage of recurrence-free patients was not significant between the two groups (P = 0.2257). Mean fever and parasite clearance time of ANPQ3 group were shorter than those in CQPQ14 group (P ≤ 0.001). No severe adverse effect was observed in ANPQ3 group, but five (3.9%) patients had acute haemolysis in CQPQ14 group (P = 0.013). Medication percentage of ANPQ3 group was significantly higher than that of CQPQ14 group (P < 0.0001).

Conclusions

Both ANPQ3 and CQPQ14 promised clinical cure efficacy, and the radical cure efficacy was similar between the ANPQ3 and CQPQ14 group. ANPQ3 clears fever and parasites faster than CQPQ14. ANPQ3 is safer and shows better patient adherence to the regimen for treatment of P. vivax malaria along the China-Myanmar border.

Trial registration: ChiCTR-INR-17012523. Registered 31 August 2017, https://www.chictr.org.cn/showproj.html?proj=21352

Graphical Abstract
Role of sex in immune response and epigenetic mechanisms
Authors: Bhattacharya Sombodhi , Sadhukhan Debasmita , Saraswathy Radha
Published: January 2024

The functioning of the human immune system is highly dependent on the sex of the individual, which comes by virtue of sex chromosomes and hormonal differences. Epigenetic mechanisms such as X chromosome inactivation, mosaicism, skewing, and dimorphism in X chromosome genes and Y chromosome regulatory genes create a sex-based variance in the immune response between males and females. This leads to differential susceptibility in immune-related disorders like infections, autoimmunity, and malignancies. Various naturally available immunomodulators are also available which target immune pathways containing X chromosome genes.
PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis
Authors: Straube Johanna , Bukhari Shoiab , Lerrer Shalom , Winchester Robert J. , Gartshteyn Yevgeniya , Henick Brian S. , Dragovich Matthew A. , Mor Adam
Published: January 2024

Background

PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in T cell activation and enhanced immune response to tumors and pathogens. Reciprocally, despite a decade of research, approaches to treat autoimmunity with PD-1 agonists have only had limited successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor.

Methods

We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets.

Results

Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, identified an additional 1112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that the most significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Backgating these genes to canonical cytotoxic T cell signatures revealed PD-1+ HLA-DRHIGH KLRG1LOW T cells as a novel inflammatory subset of T cells.

Conclusions

We concluded that PD-1+ HLA-DRHIGH KLRG1LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.
Exploring a holistic training program on tactical behavior and psychological components of elite soccer players throughout competition season: a pilot study
Authors: Tassi Juan M. , Nobari Hadi , García Jesús Diaz , Rubio Ana , Gajardo Miguel Ángel López , Manzano David , García-Calvo Tomás
Published: January 2024

This study aimed to assess the effects of a training program, considering an ecological/holistic perspective, on both tactical behavior (i.e., principles of play; PP) and psychological aspects (i.e., emotional, and cognitive components) in elite soccer teams consisting of players from the U23 and U21 age groups. The participants were 46 players from the under U-23 and U-21 teams from the same club and the first division of Argentina. A quasi-experimental design was examined after five weeks of intervention through integrated training tasks, where psychological factors were used for the development of the tactical principles of the game. Two evaluations of the improvement of game principles were performed before and after the intervention. The results showed significant changes and differences in both teams concerning the PP during the post-intervention period. Specifically, the results show significant group-by-time interactions with an increase in the percentage of tactical actions and behaviors performed during the competitions in two game principles analyzed in both teams. There were significant in the group-by-time interactions for PP 3 (i.e., the first option to pass forward; p ≤ 0.001, F = 58.96, ηp2 = 0.88) and also, significant changes were in PP 4 (i.e., immediate pressure when losing the ball) through the main effect of time (p ≤ 0.001, F = 105.41, ηp2 = 0.93) and group by time interactions (p = 0.002, F = 20.08, ηp2 = 0.72). In both groups, there were significant changes in post hoc analysis (PP3: U21: p = 0.039 vs. U23: p ≤ 0.001) and (PP4: U21: p = 0.006 vs. U23: p = 0.001). It seems the strategies and constraints used, tactical components, and integrated into the psychological aspects during specific soccer training tasks can help improve the tactical behaviors of both teams in a competition associated with the PP of a soccer team.
Kitesurfing and snowkiting injuries in Norway: a retrospective study
Authors: Torland Venke , Thomassen Øyvind , Østerås Øyvind
Published: January 2024

Background

Kiteboarding (kitesurfing on water and snowkiting) is a fairly new sport and is defined as a high-risk sport. The injury rate has been reported to be between 6 and 9 per 1000 h. The aim of the study was to identify and describe kiteboarding-related injuries in Norway over a five-year period.

Methods

We used “snowball sampling” to identify kiteboarding accidents in a retrospective study. In addition, we conducted structural searches in the National Air Ambulance Service and Search and Rescue Helicopter patient record databases. All included informants were interviewed. Descriptive methods were used to characterise the sample.

Results

Twenty-nine kiteboarders were included, with a total of 33 injuries. One half of the injuries to head, face and neck were cerebral concussions (n = 12). The most common type of injury was bone fractures (n = 28), followed by soft tissue injuries (n = 24). Most injuries were of moderate severity (51%) and falling from less than 5 m was the most common mechanism of injury. Operator error and lack of experience were the most frequently reported causes of accidents (82%).

Conclusions

Serious injuries occured during kiteboarding. The majority of kiteboarders reported operator error or lack of experience as the cause of their accident. Prior to kiteboarding, a course highlighting the importance in using helmet for snowkiting and both helmet and life vest in kitesurfing, should be mandatory.
Plasma metabolic profiles predict future dementia and dementia subtypes: a prospective analysis of 274,160 participants
Authors: Qiang Yi-Xuan , You Jia , He Xiao-Yu , Guo Yu , Deng Yue-Ting , Gao Pei-Yang , Wu Xin-Rui , Feng Jian-Feng , Cheng Wei , Yu Jin-Tai
Published: January 2024

Background

Blood-based biomarkers for dementia are gaining attention due to their non-invasive nature and feasibility in regular healthcare settings. Here, we explored the associations between 249 metabolites with all-cause dementia (ACD), Alzheimer’s disease (AD), and vascular dementia (VaD) and assessed their predictive potential.

Methods

This study included 274,160 participants from the UK Biobank. Cox proportional hazard models were employed to investigate longitudinal associations between metabolites and dementia. The importance of these metabolites was quantified using machine learning algorithms, and a metabolic risk score (MetRS) was subsequently developed for each dementia type. We further investigated how MetRS stratified the risk of dementia onset and assessed its predictive performance, both alone and in combination with demographic and cognitive predictors.

Results

During a median follow-up of 14.01 years, 5274 participants developed dementia. Of the 249 metabolites examined, 143 were significantly associated with incident ACD, 130 with AD, and 140 with VaD. Among metabolites significantly associated with dementia, lipoprotein lipid concentrations, linoleic acid, sphingomyelin, glucose, and branched-chain amino acids ranked top in importance. Individuals within the top tertile of MetRS faced a significantly greater risk of developing dementia than those in the lowest tertile. When MetRS was combined with demographic and cognitive predictors, the model yielded the area under the receiver operating characteristic curve (AUC) values of 0.857 for ACD, 0.861 for AD, and 0.873 for VaD.

Conclusions

We conducted the largest metabolome investigation of dementia to date, for the first time revealed the metabolite importance ranking, and highlighted the contribution of plasma metabolites for dementia prediction.
Rare, late onset of immune checkpoint inhibitor-induced type 1 diabetes mellitus in a patient with small-cell lung cancer treated with serplulimab: a case report and review of the literature
Authors: Ning Peng , Liu Shilan , Cao Hongyi
Published: January 2024

Background

As a newly approved immune checkpoint inhibitor in China, serplulimab has been widely used in the immunotherapy of tumors. However, the immune-related adverse events of immune checkpoint inhibitors should not be ignored. Although immune checkpoint inhibitor-induced type 1 diabetes mellitus is a rare complication, it may cause diabetic ketoacidosis and endanger the lives of patients.

Case presentation

This case report describes a 55-year-old male of Han nationality from China diagnosed with small-cell lung cancer with multiple metastases who experienced an adverse event of type 1 diabetes mellitus 68 weeks after receiving serplulimab therapy. The patient presented with typical symptoms of diabetic ketoacidosis, including severe thirst, nausea, vomiting, deep respirations, and stupor. Despite the absence of diabetes-related autoantibodies, the patient had extremely low levels of insulin and C-peptide release. Other potential causes of diabetes were ruled out, confirming the condition as serplulimab-induced immune checkpoint inhibitor-induced type 1 diabetes mellitus. After aggressive treatment to correct diabetic ketoacidosis, the patient’s blood glucose levels stabilized and symptoms of diabetes improved significantly, although long-term insulin maintenance therapy was necessary.

Conclusion

This case highlights a rare, late-onset adverse event of immune checkpoint inhibitor-induced type 1 diabetes mellitus that may be overlooked during treatment with serplulimab. The monitoring of blood glucose levels and early signs and symptoms of diabetes cannot be relaxed at the late stage of treatment, even if patients do not have elevated blood glucose levels before and during the middle stage of treatment.
In silico analysis of the Val66Met mutation in BDNF protein: implications for psychological stress
Authors: Shan Muhammad Adnan , Khan Muhammad Umer , Ishtiaq Warda , Rehman Raima , Khan Samiullah , Javed Muhammad Arshad , Ali Qurban
Published: January 2024

The brain-derived neurotrophic factor (BDNF) involves stress regulation and psychiatric disorders. The Val66Met polymorphism in theBDNFgene has been linked to altered protein function and susceptibility to stress-related conditions. This in silico analysis aimed to predict and analyze the consequences of the Val66Met mutation in theBDNFgene of stressed individuals. Computational techniques, including ab initio, comparative, and I-TASSER modeling, were used to evaluate the functional and stability effects of the Val66Met mutation in BDNF. The accuracy and reliability of the models were validated. Sequence alignment and secondary structure analysis compared amino acid residues and structural components. The phylogenetic analysis assessed the conservation of the mutation site. Functional and stability prediction analyses provided mixed results, suggesting potential effects on protein function and stability. Structural models revealed the importance ofBDNFin key biological processes. Sequence alignment analysis showed the conservation of amino acid residues across species. Secondary structure analysis indicated minor differences between the wild-type and mutant forms. Phylogenetic analysis supported the evolutionary conservation of the mutation site. This computational study suggests that the Val66Met mutation inBDNFmay have implications for protein stability, structural conformation, and function. Further experimental validation is needed to confirm these findings and elucidate the precise effects of this mutation on stress-related disorders.
Hand hygiene compliance in a Brazilian COVID-19 unit: the impact of moments and contact precautions
Authors: Valim Marília Duarte , Rossetto Jéssica Regina , Bortolini Juliano , Herwaldt Loreen
Published: January 2024

Background

Healthcare-associated infections are among the most common complications during hospitalization. These infections increase morbidity and mortality and they increase length of hospital stay and the cost of healthcare. The aims of our study were to monitor hand hygiene (HH) compliance, HH technique quality and factors related to HH practice among health professionals in a COVID-19 Intensive Care Unit (ICU).

Methods

An observational, prospective study. Between September and December 2021, we observed 69 healthcare professionals in an eight-bed ICU for patients with COVID-19 in midwestern Brazil. We used the WHO observation form to collect data. The dependent variable was HH compliance and independent variables were professional category, sex, HH quality (3-step technique for at least 15 s), number of HH opportunities observed, observation shift and inappropriate glove use.

Results

We observed 1185 HH opportunities. The overall compliance rate was 26.4%, but only 6.5% were performed with the correct 3-step technique for the minimum time. HH compliance was considerably lower for moments “before” tasks (6.7%; 95% CI 4.8%, 9.2%) compared with moments “after” tasks (43.8%; 95% CI 39.9%, 47.8%). The logistic model found that inappropriate glove use, night shift and physicians (p < 0.001) were associated with low HH compliance. The infrastructure analysis found that the unit had an insufficient number of alcohol-based handrub (ABHR) dispensers at the point of care and that the mechanism for activating them was poorly designed.

Conclusions

HH compliance was very low. Inappropriate glove use was associated with low compliance and the unit’s infrastructure did not support good HH practice. The fact that healthcare professionals were more likely to do HH after tasks, suggests that they use HH to protect themselves rather than the patients. Adequate infrastructure and ongoing health education with a focus on HH while caring for patients in contact precautions are essential for improving HH compliance and patient safety.