bluuebunny/crossref_metadata_2025 huggingface dataset:
Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum
Authors: Kampoun Tanyaluck , Srichairatanakool Somdet , Prommana Parichat , Shaw Philip J. , Green Judith L. , Knuepfer Ellen , Holder Anthony A. , Uthaipibull Chairat
Published: October 2022

Background

The resistance of Plasmodium falciparum to artemisinin-based (ART) drugs, the front-line drug family used in artemisinin-based combination therapy (ACT) for treatment of malaria, is of great concern. Mutations in the kelch13 (k13) gene (for example, those resulting in the Cys580Tyr [C580Y] variant) were identified as genetic markers for ART-resistant parasites, which suggests they are associated with resistance mechanisms. However, not all resistant parasites contain a k13 mutation, and clearly greater understanding of resistance mechanisms is required. A genome-wide association study (GWAS) found single nucleotide polymorphisms associated with ART-resistance in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2), and crt (chloroquine resistance transporter), in addition to k13 gene mutations, suggesting that these alleles contribute to the resistance phenotype. The importance of the FD and ARPS10 variants in ART resistance was then studied since both proteins likely function in the apicoplast, which is a location distinct from that of K13.

Methods

The reported mutations were introduced, together with a mutation to produce the k13-C580Y variant into the ART-sensitive 3D7 parasite line and the effect on ART-susceptibility using the 0−3 h ring survival assay (RSA0−3 h) was investigated.

Results and conclusion

Introducing both fd-D193Y and arps10-V127M into a k13-C580Y-containing parasite, but not a wild-type k13 parasite, increased survival of the parasite in the RSA0−3 h. The results suggest epistasis of arps10 and k13, with arps10-V127M a modifier of ART susceptibility in different k13 allele backgrounds.
Cytoplasmic delivery of siRNA using human-derived membrane penetration-enhancing peptide
Authors: Nakamura Momoko , Fujiwara Kei , Doi Nobuhide
Published: October 2022

Background

Although protein-based methods using cell-penetrating peptides such as TAT have been expected to provide an alternative approach to siRNA delivery, the low efficiency of endosomal escape of siRNA/protein complexes taken up into cells by endocytosis remains a problem. Here, to overcome this problem, we adopted the membrane penetration-enhancing peptide S19 from human syncytin 1 previously identified in our laboratory.

Results

We prepared fusion proteins in which the S19 and TAT peptides were fused to the viral RNA-binding domains (RBDs) as carrier proteins, added the RBD-S19-TAT/siRNA complex to human cultured cells, and investigated the cytoplasmic delivery of the complex and the knockdown efficiency of target genes. We found that the intracellular uptake of the RBD-S19-TAT/siRNA complex was increased compared to that of the RBD-TAT/siRNA complex, and the expression level of the target mRNA was decreased. Because siRNA must dissociate from RBD and bind to Argonaute 2 (Ago2) to form the RNA-induced silencing complex (RISC) after the protein/siRNA complex is delivered into the cytoplasm, a dilemma arises: stronger binding between RBD and siRNA increases intracellular uptake but makes RISC formation more difficult. Thus, we next prepared fusion proteins in which the S19 and TAT peptides were fused with Ago2 instead of RBD and found that the efficiencies of siRNA delivery and knockdown obtained using TAT-S19-Ago2 were higher than those using TAT-Ago2. In addition, we found that the smallest RISC delivery induced faster knockdown than traditional siRNA lipofection, probably due to the decreased time required for RISC formation in the cytoplasm.

Conclusion

These results indicated that S19 and TAT-fused siRNA-binding proteins, especially Ago2, should be useful for the rapid and efficient delivery of siRNA without the addition of any endosome-disrupting agent.
Hyper-responsiveness to warfarin in a young patient with the VKORC1 -1639GA/CYP2C9*1*46 genotype: a case report
Authors: Aldiban Weam , Altawil Yara , Hussein Samir , Aljamali Majd , Youssef Lama A.
Published: October 2022

Background

Warfarin is the most widely used oral anticoagulant; nevertheless, dosing of warfarin is problematic for clinicians worldwide. Inter-individual variability in response to warfarin is attributed to genetic as well as non-genetic factors. Pharmacogenomics studies have identified variants in CYP2C9 and VKORC1 genes as significant predictors of warfarin dose, however, phenotypes of rare variants are not well characterized.

Case presentation

We report a case of hyper-responsiveness to warfarin in a 22-year-old outpatient with Crohn's disease who presented with a swollen, red, and painful left calf. Deep venous thrombosis (DVT) in the left lower extremity was confirmed via ultrasonography, and hence, anticoagulation therapy of heparin and concomitant warfarin was initiated. Warfarin dose of 7.5 mg/day was estimated by the physician based on clinical factors. Higher than the expected international normalized ratio (INR) value of 4.5 necessitated the reduction of the warfarin dose to 5 and eventually to 2.5 mg/day to reach a therapeutic INR value of 2.6. Pharmacogenetic profiling of the VKORC1 -1639G > A and CYP2C9 *2, *3, *4, *5, *8, *14, *20, *24, *26, *33, *40, *41, *42, *43, *45, *46, *55, *62, *63, *66, *68, *72, *73 and *78 revealed a VKORC1-1639GA/CYP2C9*1*46 genotype. The lower catalytic activity of the CYP2C9*46 (A149T) variant was previously reported in in vitro settings.

Conclusions

This is the first report on a case of warfarin hyper-responsive phenotype of a patient with the heterozygous CYP2C9*1*46 polymorphism.
Bone marrow mesenchymal stem cells regulate the dysfunction of NK cells via the T cell immunoglobulin and ITIM domain in patients with myelodysplastic syndromes
Authors: Liu Zhaoyun , Guo Yixuan , Huang Lei , Jia Yue , Liu Hui , Peng Fengping , Duan Lixiang , Zhang Hongkai , Fu Rong
Published: October 2022

Background

Myelodysplastic syndrome (MDS) is a clonal disease of hematopoietic cells, characterized by hematopoietic cell hematopoiesis and a high risk of transformation into acute myeloid leukemia (AML). Although the underlying mechanism is unclear, MDS is often associated with immune system disorders, especially cellular immune abnormalities. We analyzed the number of lymphocyte subsets by flow cytometry assay and explored the alteration of lymphocyte subsets in MDS.

Methods

Healthy controls, inpatients with primary MDS and patients with AML diagnosed from January 2017 to July 2021 were included. Flow cytometry assays were used to study lymphocyte subsets obtained from the bone marrow of the participants as well as changes in natural killer (NK) cell function. One-way analysis of variance and Student’s t-test were used to analyze the data.

Results

We found a reduction in the number and function of NK cells in patients with MDS. By further measuring the activating and inhibitory receptors on the surface of NK cells, we found that the T cell immunoglobulin and ITIM domain (TIGIT) was the highest expressed marker on NK cells. Additionally, the expression of CD155, which is the ligand of TIGIT, was significantly higher than expressions of CD112 and CD113 on bone marrow mesenchymal stem cells (BMSCs).

Conclusions

The co-culture results of BMSCs and NK cells demonstrated that BMSCs regulate NK cells through the TIGIT/CD155 interaction, indicating that NK cells play a vital role in MDS progression. BMSCs regulate the function of NK cells via TIGIT/CD155.
Early remission in multiple sclerosis is linked to altered coherence of the Cerebellar Network
Authors: Tahedl Marlene , Levine Seth M. , Weissert Robert , Kohl Zacharias , Lee De-Hyung , Linker Ralf A. , Schwarzbach Jens V.
Published: October 2022

Background

The development of permanent disability in multiple sclerosis (MS) is highly variable among patients, and the exact mechanisms that contribute to this disability remain unknown.

Methods

Following the idea that the brain has intrinsic network organization, we investigated changes of functional networks in MS patients to identify possible links between network reorganization and remission from clinical episodes in MS. Eighteen relapsing–remitting MS patients (RRMS) in their first clinical manifestation underwent resting-state functional MRI and again during remission. We used ten template networks, identified from independent component analysis, to compare changes in network coherence for each patient compared to those of 44 healthy controls from the Human Connectome Project test–retest dataset (two-sample t-﻿test of pre-post differences). Combining a binomial test with Monte Carlo procedures, we tested four models of how functional coherence might change between the first clinical episode and remission: a network can change its coherence (a) with itself (“one-with-self”), (b) with another network (“one-with-other”), or (c) with a set of other networks (“one-with-many”), or (d) multiple networks can change their coherence with respect to one common network (“many-with-one”).

Results

We found evidence supporting two of these hypotheses: coherence decreased between the Executive Control Network and several other networks (“one-with-many” hypothesis), and a set of networks altered their coherence with the Cerebellar Network (“many-with-one” hypothesis).

Conclusion

Given the unexpected commonality of the Cerebellar Network’s altered coherence with other networks (a finding present in more than 70% of the patients, despite their clinical heterogeneity), we conclude that remission in MS may result from learning processes mediated by the Cerebellar Network.
Transcriptome-based network analysis related to M2-like tumor-associated macrophage infiltration identified VARS1 as a potential target for improving melanoma immunotherapy efficacy
Authors: Wu Zhengquan , Lei Ke , Li Huaizhi , He Jiali , Shi Enxian
Published: October 2022

Rationale

The M2-like tumor-associated macrophages (TAMs) are independent prognostic factors in melanoma.

Methods

We performed weighted gene co-expression network analysis (WGCNA) to identify the module most correlated with M2-like TAMs. The Cancer Genome Atlas (TCGA) patients were classified into two clusters that differed based on prognosis and biological function, with consensus clustering. A prognostic model was established based on the differentially expressed genes (DEGs) of the two clusters. We investigated the difference in immune cell infiltration and immune response-related gene expression between the high and low risk score groups.

Results

The risk score was defined as an independent prognostic value in melanoma. VARS1 was a hub gene in the M2-like macrophage-associated WGCNA module that the DepMap portal demonstrated was necessary for melanoma growth. Overexpressing VARS1 in vitro increased melanoma cell migration and invasion, while downregulating VARS1 had the opposite result. VARS1 overexpression promoted M2 macrophage polarization and increased TGF-β1 concentrations in tumor cell supernatant in vitro. VARS1 expression was inversely correlated with immune-related signaling pathways and the expression of several immune checkpoint genes. In addition, the VARS1 expression level helped predict the response to anti-PD-1 immunotherapy. Pan-cancer analysis demonstrated that VARS1 expression negatively correlated with CD8 T cell infiltration and the immune response-related pathways in most cancers.

Conclusion

We established an M2-like TAM-related prognostic model for melanoma and explored the role of VARS1 in melanoma progression, M2 macrophage polarization, and the development of immunotherapy resistance.
Case report: BA.1 subvariant showing a BA.2-like pattern using a variant-specific PCR assay due to a single point mutation downstream the spike 69/70 deletion
Authors: Daviña-Nuñez Carlos , Pérez-Castro Sonia , Martínez-Lamas Lucía , Cabrera-Alvargonzález Jorge Julio , Rey-Cao Sonia , Carballo-Fernandez Raquel , Godoy-Diz Montse , López-Bóveda Leticia , del Campo-Pérez Victor , Suárez-Luque Silvia , Regueiro-García Benito
Published: October 2022

Background:

SARS-CoV-2 variant tracking is key to the genomic surveillance of the COVID-19 pandemic. While next-generation sequencing (NGS) is commonly used for variant determination, it is expensive and time-consuming. Variant-specific PCR (vsPCR) is a faster, cheaper method that detects specific mutations that are considered variant-defining. These tests usually rely on specific amplification when a mutation is present or a specific melting temperature peak after amplification.

Case presentation:

A discrepant result between vsPCR and NGS was found in seventeen SARS-CoV-2 samples from Galicia, Spain. A cluster of BA.1 Omicron SARS-CoV-2 variant showed a BA.2-like melting temperature pattern due to a point mutation (C21772T) downstream the deletion of the spike amino acids 69/70. As the 69/70 deletion is widely used for differentiation between BA.1 and BA.2 by vsPCR, C21772T can cause BA.1 samples to be misinterpreted as BA.2. Over a thousand BA.1 sequences in the EpiCoV database contain this mutation.

Conclusions:

To our knowledge, this is the first case of a point mutation causing a vsPCR algorithm to misclassify BA.1 samples as BA.2. This is an example of how mutations in the probe target area of vsPCR tests based on melting curve analysis can lead to variant misclassification. NGS confirmation of vsPCR results is relevant for the accuracy of the epidemiological surveillance. In order to overcome the possible impact of novel mutations, diagnostic tools must be constantly updated.
Performance of the nonstructural 1 Antigen Rapid Test for detecting all four DENV serotypes in clinical specimens from Bangkok, Thailand
Authors: Poltep Kanaporn , Phadungsombat Juthamas , Kosoltanapiwat Nathamon , Hanboonkunupakarn Borimas , Wiriyarat Witthawat , Suwanpakdee Sarin , Prompiram Phirom , Nakayama Emi E. , Suzuki Keita , Iwamoto Hisahiko , Shioda Tatsuo , Leaungwutiwong Pornsawan
Published: October 2022

Background:

Dengue is an arboviral disease that has a large effect on public health in subtropical and tropical countries. Rapid and accurate detection of dengue infection is necessary for diagnosis and disease management. We previously developed highly sensitive immunochromatographic devices, the TKK 1st and TKK 2nd kits, based on dengue virus (DENV) nonstructural protein 1 detection. However, these TKK kits were evaluated mainly using DENV type 2 clinical specimens collected in Bangladesh, and further validation using clinical specimens of other serotypes was needed.

Methods:

In the present study, one of the TKK kits, TKK 2nd, was evaluated using 10 DENV-1, 10 DENV-2, 4 DENV-3, 16 DENV-4, and 10 zika virus-infected clinical specimens collected in Bangkok, Thailand.

Results:

The TKK 2nd kit successfully detected all four DENV serotypes in patient serum specimens and did not show any cross-reactivities against zika virus serum specimens. The IgM and/or IgG anti-DENV antibodies were detected in seven serum specimens, but did not seem to affect the results of antigen detection in the TKK 2nd kit.

Conclusion:

The results showed that the TKK 2nd kit successfully detected all four DENV serotypes in clinical specimens and confirmed the potential of the kit for dengue diagnosis in endemic countries.
The levels of TGFβ1, VEGF, PDGF-BB, and PF4 in platelet-rich plasma of professional soccer players: a cross-sectional pilot study
Authors: Mochizuki Tomoharu , Ushiki Takashi , Watanabe Satoshi , Omori Go , Kawase Tomoyuki
Published: October 2022

Background

Regenerative therapy using platelet-rich plasma (PRP), a rich source of growth factors, has become popular in orthopedic sports medicine. Elite athletes prefer PRP therapy for their injured muscles and tendons primarily to avoid the possible risks of surgical treatment. However, the clinical effectiveness of PRP therapy in elite athletes compared to that in non-athletes remains unknown. Therefore, to investigate the effectiveness of PRP therapy in professional athletes (pro-athletes), we focused on the quality of PRP preparations and compared the levels of bioactive molecules between pro-athletes and non-athletes.

Methods

PRP was prepared from healthy, non-smoking male professional soccer players (pro-athletes) (n = 22) and non-athletes (VEGF: n = 34, others: n = 38). The levels of TGFβ1, PDGF-BB, VEGF, and PF4 were determined using ELISA kits. Polyphosphate was probed with 4’,6-diamidino-2-phenylindole and monitored using a fluorometer. The body composition of the donors was determined using a bathroom weighing scale.

Results

The levels of TGFβ1 and VEGF were significantly lower in pro-athletes than in non-athletes, whereas PF4 levels were significantly higher in pro-athletes. No significant difference was found in PDGF-BB levels between these groups. Biomolecule levels were not correlated with polyphosphate levels.

Conclusion

TGFβ1, VEGF, and PDGF-BB levels in pro-athletes were not higher than those in non-athletes. These findings suggest that growth factor levels in PRP may not be a predominant determinant of the clinical effectiveness of PRP therapy in pro-athletes. Increased PF4 levels in pro-athletes suggest an immunological function of PRP that may positively influence tissue regeneration.
Clinical features and outcomes of congenital chylothorax: a single tertiary medical center experience in China
Authors: Wang Beibei , Feng Yun , Guo Yan , Kan Qing , Zou Yunsu , Wu Yue , Zheng Mingming , Cheng Rui
Published: October 2022

Objective

Congenital chylothorax (CC) is an uncommon congenital disease. The objective of this study was to analyze the clinical features, treatment, and outcome of infants with CC in a Chinese tertiary medical center.

Methods

CC was defined as a non-traumatic pleural effusion with ≥ 80% lymphocytes detected before birth or within 28 days after birth. Clinical data were collected in CC infants discharged from June 2017 to March 2021.

Results

A total of 24 CC infants were discharged during the study period, accounting for 67% of congenital pleural effusions. The median gestational age at birth was 36+4 weeks (range 29+5–41 weeks) and the birth weight was 3025 g (range 1850–4250 g). Twenty-one infants were diagnosed antenatally. The median gestational age at the time of diagnosis was 30+3 weeks (range 24–36+6 weeks). Nine infants presented with hydrops fetalis; 18 were bilateral. Prenatal interventions were performed in 13 fetuses. Nine infants (38%) had birth asphyxia. Compared with the infants without hydrops fetalis, the infants with CC and hydrops fetalis had lower Apgar scores at 1 and 5 min (P < 0.05) and a lower gestational age at birth (P < 0.05). Postnatally, 17 infants required continuous pleural drainage for 10 days (range 2–30 days). Analysis of the pleural effusion showed a higher cell count, lymphocyte fraction, and protein content after enteral feeding (P < 0.05). Fifteen infants required mechanical ventilation; 9 did not require any respiratory support. Ten infants received a delayed feeding strategy and 17 received a medium-chain triglyceride (MCT) formula. Only 1 infant received octreotide therapy. Twenty-one infants survived and 3 died. The main cause of death was pulmonary dysplasia. The duration of hospital stay in survivors was 21.5 days (range 10–43) days. For infants with CC and hydrops fetalis, prenatal therapy shortened the duration of pleural drainage and the length of hospital stay (P < 0.05).

Conclusion

CC is the most common cause of congenital pleural effusions. The poor prognosis is mainly associated with prematurity, hydrops fetalis, and pulmonary dysplasia. Prenatal intervention may improve the outcome of infants with hydrops fetalis.
Sanfilippo syndrome: consensus guidelines for clinical care
Authors: Muschol Nicole , Giugliani Roberto , Jones Simon A. , Muenzer Joseph , Smith Nicholas J. C. , Whitley Chester B. , Donnell Megan , Drake Elise , Elvidge Kristina , Melton Lisa , O’Neill Cara ,   MPS III Guideline Development Group
Published: October 2022

Sanfilippo syndrome is a group of rare, complex, and progressive neurodegenerative lysosomal storage disorders that is characterized by childhood dementia. The clinical management of patients with progressive neurological decline and multisystem involvement requires a multidisciplinary team with experience in the management of neurodegenerative disorders. Best practice guidelines for the clinical management of patients with these types of rare disorders are critical to ensure prompt diagnosis and initiation of appropriate care. However, there are no published standard global clinical care guidelines for patients with Sanfilippo syndrome. To address this, a literature review was conducted to evaluate the current evidence base and to identify evidence gaps. The findings were reviewed by an international steering committee composed of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. This review distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations for how to approach common management challenges and appropriate monitoring schedules in the care of patients with Sanfilippo syndrome.
Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel
Authors: Chen Jia , Li Hong , Guo Sicheng , Yang Zhe , Sun Shaoping , Zeng JunJie , Gou Hongjuan , Chen Yechang , Wang Feng , Lin Yanping , Huang Kun , Yue Hong , Ma Yuting , Lin Yubi
Published: October 2022

Background

Brugada syndrome (Brs) and long QT syndrome (LQTs) are the most observed “inherited primary arrhythmia syndromes” and “channelopathies”, which lead to sudden cardiac death.

Methods

Detailed clinical information of Brs and LQTs patients was collected. Genomic DNA samples of peripheral blood were conducted for whole-exome sequencing on the Illumina HiSeq 2000 platform. Then, we performed bioinformatics analysis for 200 genes susceptible to arrhythmias and cardiomyopathies. Protein interaction and transcriptomic co-expression were analyzed using the online website and GTEx database.

Results

All sixteen cases of Brs and six cases of LQTs were enrolled in the current study. Four Brs carried known pathogenic or likely pathogenic of single-point mutations, including SCN5A p.R661W, SCN5A p.R965C, and KCNH2 p.R692Q. One Brs carried the heterozygous compound mutations of DSG2 p.F531C and SCN5A p.A1374S. Two Brs carried the novel heterozygous truncated mutations (MAF < 0.001) of NEBL (p.R882X) and NPPA (p.R107X), respectively. Except for the indirect interaction between NEBL and SCN5A, NPPA directly interacts with SCN5A. These gene expressions had a specific and significant positive correlation in myocardial tissue, with high degrees of co-expression and synergy. Two Brs carried MYH7 p.E1902Q and MYH6 p.R1820Q, which were predicted as "damaging/possibly damaging" and "damaging/damaging" by Polyphen and SIFT algorithm. Two LQTs elicited the pathogenic single splicing mutation of KCNQ1 (c.922-1G > C). Three LQTs carried a single pathogenic mutation of SCN5A p.R1880H, KCNH2 p.D161N, and KCNQ1 p.R243S, respectively. One patient of LQTs carried a frameshift mutation of KCNH2 p. A188Gfs*143.

Conclusions

The truncated mutations of NEBL (p.R882X) and NPPA (p.R107X) may induce Brugada syndrome by abnormally affecting cardiac sodium channel. SCN5A (p.R661W, p.R965C and p.A1374S) and KCNH2 (p.R692Q) may cause Brugada syndrome, while SCN5A (p.R1880H), KCNQ1 (c.922-1G > C and p.R243S) and KCNH2 (p.D161N and p.A188Gfs*143) may lead to long QT syndrome.
Expert Group Consensus on early diagnosis and management of infantile-onset pompe disease in the Gulf Region
Authors: Al-Hassnan Zuhair , Hashmi Nadia Al , Makhseed Nawal , Omran Tawfeg Ben , Al Jasmi Fatma , Teneiji Amal Al
Published: October 2022

Background:

Infantile-onset Pompe disease (IOPD) is a rare and devastating, autosomal recessive lysosomal storage disorder that manifests immediately after birth. In severe IOPD cases, complete/almost-complete acid alpha-glucosidase enzyme deficiency is observed. Considering the rapid progression of the disease, timely diagnosis and treatment are important; even slight delays can remarkably alter the course of the disease. Enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is safe and beneficial for IOPD patients. However, there is heterogeneity in the patient response to ERT. The factors influencing treatment effectiveness include the patient’s age at the time of treatment initiation, pre-existing muscle damage, and cross-reactive immunologic material (CRIM) status at baseline. Immunomodulation along with ERT is the recently developed therapeutic approach that has been included in the therapeutic armamentarium of IOPD for optimizing clinical benefits, particularly in CRIM-negative IOPD patients. However, there is a dearth of published data on the early diagnosis and clinical position of the immunomodulation protocol along with ERT in the treatment of IOPD in the Gulf region.

Methods and results:

Expert panel meetings, involving six experts from the Kingdom of Saudi Arabia, Kuwait, Oman, Qatar, and the United Arab Emirates, were convened to develop consensus-based recommendations addressing current diagnostic and management challenges for patients with IOPD in the Gulf region. Furthermore, this consensus guideline may be implemented in clinical practice for the timely diagnosis and management of patients with IOPD.

Conclusion:

The expert consensus will help clinicians to make appropriate and timely decisions regarding immunomodulation initiation and ERT treatment in IOPD patients in the Gulf region.
Parental coping with uncertainties along the severe combined immunodeficiency journey
Authors: Kutsa Oksana , Andrews Sara M. , Mallonee Erin , Gwaltney Angela , Creamer Alissa , Han Paul K. J. , Raspa Melissa , Biesecker Barbara B.
Published: October 2022

Background

Severe combined immunodeficiency (SCID) is a group of rare genetic disorders that cause disruption in immune system functioning. Parents of children with SCID experience many uncertainties related to their child’s diagnosis, treatment, recovery, and quality of life. To fully understand parents’ experiences throughout their SCID journey, it is important to explore the stressors generated by such uncertainties and how parents cope with these stressors.

Methods

We conducted 26 in-depth interviews with parents whose child was diagnosed with SCID or a SCID-like condition through newborn screening. The interviews explored uncertainties related to their child’s diagnosis and how parents coped with these uncertainties. Transcripts were generated from the interviews and analyzed using an inductive content analysis approach which included data immersion, generation and assignment of codes, and interpretation.

Results

Parents used a variety of behavioral, cognitive, and affective coping strategies which evolved throughout their SCID journeys. Some parents reported coping by playing an active role in their child’s treatment, which included reaching out to other SCID parents or seeking second medical opinions. Other types of coping included establishing house hygiene rules, thinking positively about the child’s treatment progress, and relying on family members for help. These coping strategies were both deliberate and intuitive. Participants also described their struggles in coping with stressors related to their child’s health and survival. They reported difficulty in processing their emotions and experiencing denial and guilt related to their child’s diagnosis. Some parents adapted to ongoing uncertainties through such strategies as positive thinking, self-reflection, and relying on family and community. With successful adaptation, parents emphasized that they continue to use these strategies today.

Conclusion

Our assessment revealed that parents of children diagnosed with SCID use a variety of behavioral, cognitive, and affective approaches to cope with SCID uncertainties. Although parents reported challenges in coping with SCID uncertainties, they also reported finding ways to overcome these stressors and establish patterns of effective coping. Findings from our study can serve as a guide for parents whose child was newly diagnosed with SCID and for providers such as social workers, genetic counselors, and psychologists.
Transitioning of protein substitutes in patients with phenylketonuria: evaluation of current practice
Authors: Yilmaz Ozlem , Pinto Alex , Daly Anne , Ashmore Catherine , Evans Sharon , Yabanci Ayhan Nurcan , MacDonald Anita
Published: October 2022

Background

In children with phenylketonuria (PKU), transitioning protein substitutes at the appropriate developmental age is essential to help with their long-term acceptance and ease of administration. We assessed the parental experiences in transitioning from a second stage to third stage liquid or powdered protein substitute in patients with PKU.

Results

Sixteen interviews (23 open-ended questions) were carried out with parents/caregivers of children with PKU (8 females, 50%) with a median age of 8 years (range 5–11 years), continuously treated with diet, and on a third stage protein substitute. Parents/caregivers identified common facilitators and barriers during the third stage protein substitute transition process. The main facilitators were: child and parent motivation, parent knowledge of the transition process, a role model with PKU, low volume and easy preparation of the third stage protein substitute (liquid/powder), anticipation of increasing child independence, lower parent workload, attractive packaging, better taste and smell, school and teacher support, dietetic plans and guidance, PKU social events, child educational materials and written resources. The main barriers were child aversion to new protein substitutes, poor child behaviour, child aged > 5 years, parental fear of change, the necessity for  parental time and persistence, loss of parental control, high product volume, different taste, smell, and texture of new protein substitutes, and peer bullying.

Conclusion

A stepwise, supportive approach is necessary when transitioning from second to third stage protein substitutes in PKU. Future studies are needed to develop guidance to assist parents/caregivers, health professionals, and teachers during the transition process.
Remarkably low host specificity in the bat fly Penicillidia fulvida (Diptera: Nycteribiidae) as assessed by mitochondrial COI and nuclear 28S sequence data
Authors: Verrett Taylor B. , Webala Paul W. , Patterson Bruce D. , Dick Carl W.
Published: October 2022

Background

The recognition and delineation of morphologically indistinguishable cryptic species can have broad implications for wildlife conservation, disease ecology and accurate estimates of biodiversity. Parasites are intriguing in the study of cryptic speciation because unique evolutionary pressures and diversifying factors are generated by ecological characteristics of host-parasite relationships, including host specificity. Bat flies (Diptera: Nycteribiidae and Streblidae) are obligate, hematophagous ectoparasites of bats that generally exhibit high host specificity. One rare exception is Penicillidia fulvida (Diptera: Nycteribiidae), an African bat fly found in association with many phylogenetically distant hosts. One explanation for P. fulvida’s extreme polyxeny is that it may represent a complex of host-specific yet cryptic species, an increasingly common finding in molecular genetic studies of supposed generalist parasites.

Methods

A total of 65 P. fulvida specimens were collected at 14 localities across Kenya, from bat species representing six bat families. Mitochondrial cytochrome c oxidase subunit 1 (COI) and nuclear 28S ribosomal RNA (rRNA) sequences were obtained from 59 specimens and used to construct Bayesian and maximum likelihood phylogenies. Analysis of molecular variance was used to determine how genetic variation in P. fulvida was allocated among host taxa.

Results

The 28S rRNA sequences studied were invariant within P. fulvida. Some genetic structure was present in the COI sequence data, but this could be more parsimoniously explained by geography than host family.

Conclusions

Our results support the status of P. fulvida as a rare example of a single bat fly species with primary host associations spanning multiple bat families. Gene flow among P. fulvida utilizing different host species may be promoted by polyspecific roosting behavior in bats, and host preference may also be malleable based on bat assemblages occupying shared roosts. The proclivity of generalist parasites to switch hosts makes them more likely to vector or opportunistically transmit pathogens across host species boundaries. Consequently, the presence of polyxenous bat flies is an important consideration to disease ecology as bat flies become increasingly known to be associated with bat pathogens.

Graphical Abstract
The lung microbiome, peripheral gene expression, and recurrence-free survival after resection of stage II non-small cell lung cancer
Authors: Peters Brandilyn A. , Pass Harvey I. , Burk Robert D. , Xue Xiaonan , Goparaju Chandra , Sollecito Christopher C. , Grassi Evan , Segal Leopoldo N. , Tsay Jun-Chieh J. , Hayes Richard B. , Ahn Jiyoung
Published: October 2022

Background

Cancer recurrence after tumor resection in early-stage non-small cell lung cancer (NSCLC) is common, yet difficult to predict. The lung microbiota and systemic immunity may be important modulators of risk for lung cancer recurrence, yet biomarkers from the lung microbiome and peripheral immune environment are understudied. Such markers may hold promise for prediction as well as improved etiologic understanding of lung cancer recurrence.

Methods

In tumor and distant normal lung samples from 46 stage II NSCLC patients with curative resection (39 tumor samples, 41 normal lung samples), we conducted 16S rRNA gene sequencing. We also measured peripheral blood immune gene expression with nanoString®. We examined associations of lung microbiota and peripheral gene expression with recurrence-free survival (RFS) and disease-free survival (DFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression, and examined predictive accuracy using time-dependent receiver operating characteristic (ROC) curves.

Results

Over a median of 4.8 years of follow-up (range 0.2–12.2 years), 43% of patients experienced a recurrence, and 50% died. In normal lung tissue, a higher abundance of classes Bacteroidia and Clostridia, and orders Bacteroidales and Clostridiales, were associated with worse RFS, while a higher abundance of classes Alphaproteobacteria and Betaproteobacteria, and orders Burkholderiales and Neisseriales, were associated with better RFS. In tumor tissue, a higher abundance of orders Actinomycetales and Pseudomonadales were associated with worse DFS. Among these taxa, normal lung Clostridiales and Bacteroidales were also related to worse survival in a previous small pilot study and an additional independent validation cohort. In peripheral blood, higher expression of genes TAP1, TAPBP, CSF2RB, and IFITM2 were associated with better DFS. Analysis of ROC curves revealed that lung microbiome and peripheral gene expression biomarkers provided significant additional recurrence risk discrimination over standard demographic and clinical covariates, with microbiome biomarkers contributing more to short-term (1-year) prediction and gene biomarkers contributing to longer-term (2–5-year) prediction.

Conclusions

We identified compelling biomarkers in under-explored data types, the lung microbiome, and peripheral blood gene expression, which may improve risk prediction of recurrence in early-stage NSCLC patients. These findings will require validation in a larger cohort.
First evidence of Proganochelys quenstedtii (Testudinata) from the Plateosaurus bonebeds (Norian, Late Triassic) of Frick, Canton Aargau, Switzerland
Authors: Scheyer Torsten M. , Klein Nicole , Evers Serjoscha W. , Mautner Anna-Katharina , Pabst Ben
Published: October 2022

Proganochelys quenstedtiirepresents the best-known stem turtle from the Late Triassic, with gross anatomical and internal descriptions of the shell, postcranial bones and skull based on several well-preserved specimens from Central European fossil locations. We here report on the first specimen ofP. quenstedtiifrom the Late Triassic (Klettgau Formation) Frickberg near the town of Frick, Canton Aargau, Switzerland. Similar to other Late Triassic ‘Plateosaurus-bearing bonebeds’,Proganochelysis considered to be a rare faunal element in the Swiss locality of Frick as well. The specimen, which is largely complete but was found only partially articulated and mixed with largePlateosaurusbones, overall resembles the morphology of the classical specimens from Germany. Despite being disarticulated, most skull bones could be identified and micro-computed tomography (CT) scanning of the posterior skull region reveals new insights into the braincase and neurovascular anatomy, as well as the inner ear region. These include the presence of a fenestra perilymphatica, potentially elongated cochlear ducts, and intense vascularization of small tubercles on the posterior end of the skull roof, which we interpret as horn cores. Other aspects of the skull in the braincase region, such as the presence or absence of a supratemporal remain ambiguous due to the fusion of individual bones and thus lack of visible sutures (externally and internally). Based on the size of the shell and fusion of individual elements, the specimen is interpreted as a skeletally mature animal.
Heat-labile enterotoxin enhances F4-producing enterotoxigenic E. coli adhesion to porcine intestinal epithelial cells by upregulating bacterial adhesins and STb enterotoxin
Authors: Duan Qiangde , Pang Shengmei , Feng Lili , Liu Jiaqi , Lv Linfen , Li Baoliang , Liang Yuxuan , Zhu Guoqiang
Published: October 2022

As one of the crucial enterotoxins secreted by enterotoxigenic Escherichia coli (ETEC), heat-labile enterotoxin (LT) enhances bacterial adherence both in vivo and in vitro; however, the underlying mechanism remains unclear. To address this, we evaluated the adherence of LT-producing and LT-deficient ETEC strains using the IPEC-J2 cell model. The expression levels of inflammatory cytokines and chemokines, and tight-junction proteins were evaluated in IPEC-J2 cells after infection with various ETEC strains. Further, the levels of adhesins and enterotoxins were also evaluated in F4ac-producing ETEC (F4 + ETEC) strains after treatment with cyclic AMP (cAMP). The adherence of the ΔeltAB mutant was decreased compared with the wild-type strain, whereas adherence of the 1836-2/pBR322-eltAB strain was markedly increased compared with the 1836-2 parental strain. Production of LT up-regulated the expression of TNF-α, IL-6, CXCL-8, and IL-10 genes. However, it did not appear to affect tight junction protein expression. Importantly, we found that cAMP leads to the upregulation of adhesin production and STb enterotoxin. Moreover, the F4 + ETEC strains treated with cAMP also had greater adhesion to IPEC-J2 cells, and the adherence of ΔfaeG, ΔfliC, and ΔestB mutants was decreased. These results indicate that LT enhances the adherence of F4 + ETEC due primarily to the upregulation of F4 fimbriae, flagellin, and STb enterotoxin expression and provide insights into the pathogenic mechanism of LT and ETEC.
On the class of uncertainty inequalities for the coupled fractional Fourier transform
Authors: Shah Firdous A. , Lone Waseem Z. , Nisar Kottakkaran Sooppy , Abdeljawad Thabet
Published: October 2022

The coupled fractional Fourier transform$\mathcal {F}_{\alpha ,\beta}$Fα,βis a two-dimensional fractional Fourier transform depending on two anglesαandβ, which are coupled in such a way that the transform parameters are$\gamma =(\alpha +\beta )/2$γ=(α+β)/2and$\delta =(\alpha -\beta )/2$δ=(α−β)/2. It generalizes the two-dimensional Fourier transform and serves as a prominent tool in some applications of signal and image processing. In this article, we formulate a new class of uncertainty inequalities for the coupled fractional Fourier transform (CFrFT). Firstly, we establish a sharp Heisenberg-type uncertainty inequality for the CFrFT and then formulate some logarithmic and local-type uncertainty inequalities. In the sequel, we establish several concentration-based uncertainty inequalities, including Nazarov, Amrein–Berthier–Benedicks, and Donoho–Stark’s inequalities. Towards the end, we formulate Hardy’s and Beurling’s inequalities for the CFrFT.
Energy-efficient allocation for multiple tasks in mobile edge computing
Authors: Liu Jun , Liu Xi
Published: October 2022

Mobile edge computing (MEC) allows a mobile device to offload tasks to the nearby server for remote execution to enhance the performance of user equipment. A major challenge of MEC is to design an efficient algorithm for task allocation. In contrast to previous work on MEC, which mainly focuses on single-task allocation for a mobile device with only one task to be completed, this paper considers a mobile device with multiple tasks or an application with multiple tasks. This assumption does not hold in real settings because a mobile device may have multiple tasks waiting to execute. We address the problem of task allocation with minimum total energy consumption considering multi-task settings in MEC, in which a mobile device has one or more tasks. We consider the binary computation offloading mode and formulate multi-task allocation as an integer programming problem that is strongly NP-hard. We propose an approximation algorithm and show it is a polynomial-time approximation scheme that saves the maximum energy. Therefore, our proposed algorithm achieves a tradeoff between optimality loss and time complexity. We analyze the performance of the proposed algorithm by performing extensive experiments. The results of the experiments demonstrate that our proposed approximation algorithm is capable of finding near-optimal solutions, and achieves a good balance of speed and quality.
The correlation between anxiety, depression, and vertigo: a cross-sectional study
Authors: Omara Abir , Basiouny Eman Mostafa , Shabrawy Marwa El , Shafei Reham Rafei El
Published: October 2022

Background

Dizziness, including vertigo, affects approximately 15% to over 20% of adults each year. A significant proportion of patients with vertigo develop secondary psychiatric disorders throughout their disease. On the other hand, patients with psychiatric disorders frequently report dizziness as a co-occurring symptom of their illness. The purpose of this study was to screen the prevalence of depression and anxiety indices in dizzy patients and their relation to the severity of their dizziness handicap by administering two different questionnaires: The dizziness handicap inventory (DHI) and the Hospital Anxiety and Depression Scale (HADS). 

Results

Psychological assessments revealed that 49% of the study group was normal, 29% had anxiety, 7% had depression, and 15% had both anxiety and depression. Besides, vestibular neuritis was associated with a higher mean anxiety score, whereas Meniere's disease was associated with a higher mean depression score. 

Conclusion

As this study has shown, there was a statistically significant positive correlation between anxiety and depression scores and physical, emotional, functional, and total DHI scores. Screening and treatment of co-morbid mental health disorders are critical for appropriate management of vertigo disability that leads to a higher quality of life and fewer complications.
An ab initio study on phase stability, elastic and mechanical properties of Zr-doped TiAl2 and α-TiAl3 intermetallics
Authors: Mermer Erdem , Çinici Hanifi , Uğur Gökay , Ünal Rahmi
Published: October 2022

In this study, phase stability, elastic and mechanical properties of Zr-doped TiAl2 and

intermetallics have been studied by ab initio calculations based on density functional theory. The virtual crystal approximation (VCA) method has been utilized to develop crystal structures. Calculated lattice constants and elastic properties of the unalloyed TiAl2 and

intermetallics were given and discussed. In addition, machinability index has been accounted for. Formation enthalpies, Gibbs free energies of Zr-doped compounds are lower than pure TiAl2 and

intermetallics. Bulk moduli values have been improved by Zr doping for both alloys. Ductile alloys have been obtained when Zr addition of TiAl2 and

was greater than 6.0 wt.%.
Teprotumumab-Related Hyperglycemia
Authors: Amarikwa Linus , Mohamed Abubakr , Kim Sun H , Kossler Andrea Lora , Dosiou Chrysoula
Published: October 2022

Context

Graves orbitopathy (GO) or thyroid eye disease is a potentially sight-threatening and disfiguring autoimmune disease. Teprotumumab is a monoclonal antibody against the insulin-like growth factor-I receptor that was recently approved for GO treatment. Hyperglycemia is a recognized adverse event of teprotumumab, occurring in 10% of patients in 2 recent randomized controlled trials.

Objective

Our study aimed to report the incidence, severity, management, and longitudinal glycemic changes in patients treated with teprotumumab in an academic practice cohort.

Methods

This longitudinal, observational study included all consecutive patients treated with teprotumumab between March 2020 and May 2022 at 1 institution. Hemoglobin A1c (HbA1c) was measured every 3 months.

Results

Forty-two patients with baseline normoglycemia (n = 22), prediabetes (n = 10), and diabetes (n = 10) were followed for a mean of 47.5 weeks. Overall, HbA1c increased by 0.5% at 3 months. Least-squares mean changes in HbA1c at 3 months were 1.3 (P < .001), 0.7 (P = .01), and 0.1 (P = .41) in patients with diabetes, prediabetes, and normoglycemia, respectively. Twenty-two patients (52%) had hyperglycemia, which was graded as mild, moderate, and life-threatening in 55% (12/22), 41% (9/22), and 5% (1/22) of cases, respectively. Age, pre-existing diabetes, and Hispanic and Asian race/ethnicity were significant risk factors for hyperglycemia. Among patients with hyperglycemia, 36.4% (8/22) returned to baseline glycemic status at last follow-up.

Conclusion

While effective, teprotumumab carries a significant risk of hyperglycemia, especially in patients with diabetes. Hyperglycemia may persist after stopping teprotumumab. These findings underscore the importance of guidelines for screening and management of teprotumumab-related hyperglycemia.