bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrophage inflammarafts in atherosclerosis
Authors: Li Shenglin , Navia-Pelaez Juliana M. , Choi Soo-Ho. , Miller Yury I.
Published: August 2023

Purpose of review

Advances in single cell techniques revealed a remarkable diversity in macrophage gene expression profiles in atherosclerosis. However, the diversity of functional processes at the macrophage plasma membrane remains less studied. This review summarizes recent advances in characterization of lipid rafts, where inflammatory receptors assemble, in macrophages that undergo reprogramming in atherosclerotic lesions and in vitro under conditions relevant to the development of atherosclerosis.

Recent findings

The term inflammarafts refers to enlarged lipid rafts with increased cholesterol content, hosting components of inflammatory receptor complexes assembled in close proximity, including TLR4-TLR4, TLR2-TLR1 and TLR2-CD36 dimers. Macrophages decorated with inflammarafts maintain chronic inflammatory gene expression and are primed to an augmented response to additional inflammatory stimuli. In mouse atherosclerotic lesions, inflammarafts are expressed primarily in nonfoamy macrophages and less in lipid-laden foam cells. This agrees with the reported suppression of inflammatory programs in foam cells. In contrast, nonfoamy macrophages expressing inflammarafts are the major inflammatory population in atherosclerotic lesions. Discussed are emerging reports that help understand formation and persistence of inflammarafts and the potential of inflammarafts as a novel therapeutic target.

Chronic maintenance of inflammarafts in nonfoamy macrophages serves as an effector mechanism of inflammatory macrophage reprogramming in atherosclerosis.
Techniques and Complications of Anesthesia in Pediatric Radiotherapy: A Retrospective Cohort Study
Authors: Villablanca Nicolás , Valls Nicolás , González Roberto
Published: August 2023

Background:

Anesthesia during pediatric external beam radiation therapy poses a challenge, as radiotherapy rooms are not designed for the administration of anesthesia.

Aims:

We conducted a retrospective cohort study of children who underwent radiation therapy to describe the anesthetic approach and assess anesthetic-related complications.

Materials and Methods:

Data of all, who underwent radiation therapy under general anesthesia between November 2019 and January 2021, were recorded. Data were obtained from medical records, including demographic characteristics and information, regarding the anesthetic procedure and its associated complications. We describe our protocols for preoperative assessment, anesthetic procedures, and postanesthetic discharge evaluation.

Results:

Over the reporting period, 739 sessions of general anesthesia were performed. The mean number of radiation therapy rounds per patient was 23.5 sessions. Anesthetic induction was accomplished by sevoflurane inhalation in 639 sessions (86.4%) and intravenous propofol in the remaining 13.6%. General anesthesia was maintained with sevoflurane in all cases. Anesthesia-related complications occurred in 118 sessions (15.7%). The most frequent was nausea in 48 (6.4%) cases, followed by hypotension in 38 (5.1%). Airway-related complications occurred at a low frequency (2.3%), and all were resolved successfully with positive pressure ventilation. No patient hospitalizations were required because of any anesthetic complications.

Conclusions:

Inhalation anesthesia is reliable and safe for pediatric patients undergoing radiation therapy.
Splenic Artery Embolization in a Patient With Intracranial Hemorrhage Due to Refractory Persistent Immune Thrombocytopenia
Authors: Sarper Nazan , Çam İsa , Aylan Gelen Sema , Sönmez Hafize Emine , Sakarya Güneş Ayfer , Zengin Emine
Published: August 2023

Background:

Managing intracranial bleeding in patients with refractory immune thrombocytopenia is difficult.

Observation:

A 16-year-old female refractory to prednisolone, intravenous immunoglobulin, eltrombopag, and cyclosporin exhibited heavy menstrual bleeding requiring packed red blood cell transfusions. Autoimmune antibodies were detected, indicating of lupus, and hydroxychloroquine sulfate was administered. In month 6 following the diagnosis, the patient presented with intracranial hemorrhage. Splenic artery embolization promptly increased platelets, and the patient was discharged without any neurological sequela. In month 5 of embolization, the patient’s platelet count continued to exceed 300,000/µL without any medical treatment.

Conclusions:

Splenic artery embolization is a life-saving procedure in refractory immune thrombocytopenia.
Neurologic Complications in Patients With Lymphoreticular Malignancy: A Descriptive Cohort Study
Authors: Baloda Renuka , Sharma Suvasini , Anand Rama , Mandal Piali , Parakh Nupur , Katti Bharat , Singh Varinder , Chandra Jagdish
Published: August 2023

Objectives:

The objectives of this study were to study the spectrum of neurologic complications in children with lymphoreticular malignancy (acute lymphoblastic leukemia, Hodgkin, and non-Hodgkin lymphoma) at diagnosis and during treatment and to determine the etiology of these complications.

Materials and Methods:

In this descriptive cohort study, conducted between November 2018 and March 2020, 204 children with a diagnosis of lymphoreticular malignancy were enrolled. The baseline investigations were done in all the cases. Those who developed neurological symptoms were evaluated with cerebrospinal fluid examination and radiologic and electrophysiologic studies as per indication and were managed according to standard management guidelines.

Results:

Of the 204 patients, 30 (14.7%) developed neurological complications. The majority of these complications (n=20/30; 87%) occurred during the intensive chemotherapy period. Common complications included acute methotrexate neurotoxicity (n=7), vincristine-induced neurotoxicity (n=7), central nervous system (CNS) relapse (n=4), and posterior reversible encephalopathy syndrome (n=2). L-asparaginase-induced thrombosis (n=1), intramedullary compression syndrome (n=1), CNS infection (n=2), CNS hemophagocytic lymphohistiocytosis (n=1), and steroid-induced myopathy (n=1) were also observed. The complications resolved in 21/30 (70%) patients after receiving appropriate treatment while the neurological complication persisted in 2/30 (6.7%) patients. Three patients (10%) abandoned the treatment, and 4 (13.3%) patients expired.

Conclusions:

Neurologic complications in patients with lymphoreticular malignancy are quite variable, having common presenting symptoms but varying imaging abnormalities. By close follow-up and effective treatment, the morbidity and mortality of these complications can be minimized.
The Psychosocial Impact of the COVID-19 Pandemic on Families of Children With Cancer in the Low-income Setting
Authors: Khalil Dima , Alyoussef Rasha , Al Hosni Hisham , Idriss Sahab , Ahmad Abeer , Al Rooh Sama , Ghanem Khaled M.
Published: August 2023

The coronavirus disease 2019 (COVID-19) pandemic has had a profound effect on families’ psychosocial well-being worldwide. This study aimed to investigate the pandemic’s impact on families of children with cancer in a low-income setting in Syria. The study conducted a cross-sectional survey of 50 families of children with cancer receiving treatment at a nongovernmental organization–based pediatric oncology unit in Syria. The survey used the Corona Anxiety Scale (CAS) to assess the pandemic’s impact on families’ anxiety, and other items to evaluate the financial toxicity of the strict measures implemented during the pandemic’s first months. The study’s results revealed that the COVID-19 pandemic significantly negatively impacted the psychosocial well-being of families of children with cancer in Syria. Specifically, 22% of families reported a major increase in anxiety levels (CAS of >9), and the majority of families (84%) reported excessive indirect financial costs, including travel and living expenses. The study emphasizes the significant social and psychological impact of the COVID-19 pandemic on families of children with cancer in Syria, highlighting the need for additional psychosocial interventions to mitigate future global health crises or pandemics’ impact on this vulnerable population. The interventions should prioritize promoting resilience and adaptive coping strategies.
Constitutional Mismatch Repair Deficiency Syndrome as a Cause of Numerous Malignancies in a Teenage Patient—A Case Report
Authors: Samborska Magdalena , Galli Dominika , Achkar Robert , Thambyrajah Sheanda , Derwich Katarzyna
Published: August 2023

Constitutional mismatch repair deficiency syndrome is a genetic disorder resulting from a biallelic mutation in one of the following genes: MLH1, MSH2, MSH6, or PMS2. Individuals with constitutional mismatch repair deficiency are highly predisposed to develop both hematological and solid cancers in childhood, particularly lymphoma, brain tumors, and gastrointestinal neoplasms. We report a case of a boy diagnosed with B-cell acute lymphoblastic leukemia at the age of 3. In 2013, at the age of 6, head magnetic resonance imaging revealed hamartoma and astrocytoma lesions in the central nervous system. Two years after treatment completion, a diagnosis of precursor T-cell lymphoblastic lymphoma, accompanied by the vena cava syndrome, was established and treated accordingly. During treatment, a genetic test using Sanger sequencing was performed—a biallelic mutation in the MSH6 gene was detected. The study revealed that the mutation 17-bp c.2277-2293del. was inherited from the patient’s mother. The second mutation, 5-bp c.1135_1139delAGAGA, developed inpatient de novo. At the age of 14, the diagnosis of isolated bone marrow relapse of acute lymphoblastic leukemia B-cell type was established. Due to the almost exceeded total dose of anthracyclines, the patient’s treatment included blinatumomab, and subsequently, he was qualified for allogeneic hematopoietic cell transplantation. The patient remains in complete remission for 11 months after allogeneic hematopoietic stem cell transplantation under the care of the transplant center.
Intravascular Tumor Extension and Pulmonary Tumor Embolism in Children With Solid Malignancies: Is There a Role for Inferior Vena Cava Filters?
Authors: Trinder Sarah M. , Ruhayel Sandra D. , Gottardo Nicholas G. , McLaren Clare A. , Ryan Anne L. , Roebuck Derek J.
Published: August 2023

Intravascular tumor extension is an uncommon complication of solid malignancies that, when present in the inferior vena cava (IVC), can result in fatal pulmonary tumor embolism. Currently, neoadjuvant chemotherapy and surgery are the mainstays of treatment; however, there are no consensus guidelines for management. We describe three cases of pediatric solid malignancies with associated IVC extension and pulmonary tumor embolism. We hypothesize that there is scope for IVC filter placement in such cases to mitigate the risk of fatal pulmonary tumor embolism.
Plasmablastic Lymphoma in a Human Immunodeficiency Virus-positive Child With a Suspicion of Concomitant Primary Immunodeficiency Disorder
Authors: Yaqoob Nausheen , Anis Sabiha , Mansoor Neelum , Khayyam Naema , Jamal Saba
Published: August 2023

Plasmablastic lymphoma (PBL) occurs in the setting of immunodeficiency, in association with human immunodeficiency virus (HIV) infection, in elderly patients, and in the posttransplantation state. It is exceptionally rare in children. PBL is an aggressive lymphoma with a poor prognosis. We present a case of pediatric PBL in an HIV-positive child with suspicion of a concomitant underlying immune deficiency state other than HIV. A 7-year-old girl presented to the pediatric emergency department with complaints of fever and painful swelling on the left side of her face for 15 days, associated with headache, snoring, and difficulty in breathing. She had a history of watery diarrhea, oral thrush, recurrent fever, and hospitalizations for skin infections since the age of 1 year. Histopathological findings were consistent with PBL. Her HIV RNA polymerase chain reaction was positive. She was offered chemotherapy based on the FAB/LMB 96 protocol. This case demonstrates an aggressive presentation of a rare entity, HIV-associated PBL, in a child, with underlying immunodeficiency and highlights the issues which caused a significant challenge in making the diagnosis. The presence of HIV infection and contradicting other immunologic investigations posed a dilemma in establishing an association of PBL in this child. The outcome of patients with this tumor is associated with high mortality.
Mechanical Hemolytic Anemia Associated With Mitral Valve Repair: A Case Report With Literature Review
Authors: Restivo Giulia A. , Scalzo Simona , Di Palermo Antonio
Published: August 2023

Hemolytic anemia could be caused by several conditions, depending on intrinsic or extrinsic defects of the erythrocyte. The latter group includes mechanical intravascular hemolysis, generally related to malfunctioning prosthetic heart valves or, rarely, heart valves repair.

We describe a case of a child with Down syndrome, who developed hemolytic anemia after mitral valve repair. We observed that this condition is a rare complication in pediatrics, with only 7 cases reported in literature.

Mechanical hemolysis should always be considered in the differential diagnosis of a new-onset hemolytic anemia, especially in patients with valvular heart disease, undergoing cardiac surgery.
Resiliency of the Digestive System During Aging and the Impact of Diet
Authors: Sanders Lisa M. , Goltz Shellen , Maki Kevin C.
Published: August 2023

Increases in life expectancy are contributing to rapid growth in the aging population around the globe. Aging is accompanied by physiological decline and susceptibility to age-related diseases. To enable healthy aging, it is important to understand the independent effects of aging on biological systems and how comorbidities and lifestyle factors may influence the health of these systems. The digestive system is a multifunctional set of tissues and organs that not only enable the digestion and absorption of nutrients, but also serves as a physical and immunological barrier to the external environment and the primary interface to commensal microbes. This review examined current evidence regarding the effects of aging on gastrointestinal function, including digestion, absorption, motility, microbiome, and barrier function. Overall, the digestive system is quite resilient to the normal aging process with comorbidities and other lifestyle factors contributing to most digestive health issues associated with aging. Emerging research on the gut microbiome and barrier function suggests an important role for the digestive system in the etiology of many age-related diseases and demonstrates how diet may be able to modify the effects of chronic diseases.
Concealed Homicides—A Postmortem Study and Review
Authors: Byard Roger W.
Published: August 2023

A study was undertaken at Forensic Science SA, Adelaide, South Australia, of all cases of homicide (January 2003–December 2022) where the victims' bodies had been concealed. Three hundred twenty-six homicides were identified, which included 27 cases where bodies had been deliberately hidden (8%) (age range, 2–82 years; ave, 34.9 years; M:F = 1.5:1). Deaths were due to blunt force trauma (n = 11), sharp force trauma (n = 4), asphyxia (n = 4), gunshot wound (n = 2), and a combination of drowning and asphyxia (n = 1). In 5 cases, the cause of death was not determinable. The methods of concealment (which were sometimes overlapping) included the following: dumping at a hidden/isolated location (n = 8), burial (n = 7), dismembering (n = 3), incinerating (n = 3), hiding in a wheeled garbage bin (n = 2), disposing in garbage resulting in the remains being located at waste disposal facilities (n = 2), hiding in a shed (n = 1), under a concrete floor (n = 1), in a suitcase (n = 1), in a river (n = 1), in a mine shaft (n = 1), and in a septic tank (n = 1). Although it has been asserted that concealed homicides are rarely encountered in forensic practice, the current study has demonstrated that the bodies in at least 8% of victims of homicide in South Australia have undergone some form of concealment.
Intraoperative Vasoactive Medications and Perioperative Outcomes in Liver Transplantation: A Systematic Review and Network Meta-analyses
Authors: Carrier François Martin , Girard Martin , Zuo Rui Min , Ziegler Daniela , Trottier Helen , Chassé Michaël
Published: August 2023

We conducted a systematic review and network meta-analyses evaluating the effects of different intraoperative vasoactive drugs on acute kidney injury (AKI) and other perioperative outcomes in adult liver transplant recipients. We searched multiple electronic databases using words from the “liver transplantation” and “vasoactive drug” domains. We included all randomized controlled trials conducted in adult liver transplant recipients comparing 2 different intravenous vasoactive drugs or 1 against a standard of care that reported AKI, intraoperative blood loss, or any other postoperative outcome. We conducted 4 frequentist network meta-analyses using random effect models, based on the interventions’ mechanism of action, and evaluated the quality of evidence (QoE) using Grading of Recommendations, Assessment, Development, and Evaluations recommendations. We included 9 randomized controlled trials comparing different vasopressor drugs (vasoconstrictor or inotrope), 3 comparing a somatostatin infusion (or its analogues) to a standard of care, 11 comparing different vasodilator infusions together or against a standard of care, and 2 comparing vasoconstrictor boluses at graft reperfusion. Intravenous clonidine was associated with shorter duration of mechanical ventilation, intensive care unit, and hospital length of stay (very low QoE), and some vasodilators were associated with lower creatinine level 24 h after surgery (low to very low QoE). Phenylephrine and terlipressin were associated with less intraoperative blood loss when compared with norepinephrine (low and moderate QoE). None of the vasoactive drugs improve any other postoperative outcomes, including AKI. There is still important equipoise regarding the best vasoactive drug to use in liver transplantation for most outcomes. Further studies are required to better inform clinical practice.
Non-HLA Antibodies to G Protein–coupled Receptors in Pediatric Kidney Transplant Recipients: Short- and Long-term Clinical Outcomes
Authors: Pearl Meghan H. , Chen Lucia , Zuckerman Jonathan E. , Weng Patricia L. , Chambers Eileen T. , Zhang Qiuheng , Reed Elaine F.
Published: August 2023

Background.

Angiotensin II type 1 receptor antibodies (AT1R-Abs) and endothelin-type A receptor antibodies (ETAR-Abs) are G protein–coupled receptor activating autoantibodies associated with antibody-mediated rejection, vascular pathology, increased cytokines, allograft dysfunction, and allograft loss in pediatric kidney transplant recipients in the first 2 y posttransplantation. The impact of AT1R-Ab and ETAR-Ab positivity on longer-term 5-y transplant outcomes is unknown.

Methods.

One hundred pediatric kidney transplant recipients were tested for ETAR-Ab and AT1R-Ab on serially collected blood samples in the first 2 y posttransplant. Biopsies were collected per protocol and 6, 12, and 24 mo posttransplant and at any time during the 5-y follow-up period for clinical indication. Clinical outcomes, including renal dysfunction, rejection, HLA donor-specific antibodies, and allograft loss, were assessed through 5 y posttransplantation.

Results.

AT1R-Ab or ETAR-Ab were positive in 59% of patients. AT1R-Ab or ETAR-Ab positivity was associated with greater declines in estimated glomerular filtration rate, and de novo AT1R-Ab or ETAR-Ab was associated with allograft loss in the first 2 y posttransplant. There was no association between antibody positivity and rejection, antibody-mediated rejection, or allograft loss in the first 5 y posttransplant. In a model controlled for age, sex, immunosuppression, and HLA mismatch, AT1R-Ab or ETAR-Ab positivity was significantly associated with the development of HLA donor-specific antibodies at 5 y posttransplant (odds ratio 2.87, P = 0.034).

Conclusions.

Our findings suggest temporally distinct clinical complications associated with AT1R-Ab or ETAR-Ab positivity in pediatric patients; these injury patterns are of significant interest for developing effective treatment strategies.
Three Cases of Myoclonus Secondary to Ciprofloxacin: “Ciproclonus”
Authors: Javed Hamna , Ali Hossam Tharwat , Soliman Ziad Ashraf , Caprara Ana Leticia Fornari , Rissardo Jamir Pitton
Published: August 2023

Objectives

Ciprofloxacin is a fluoroquinolone that is used for bacterial infections involving different systems. In some cases, ciprofloxacin was reported to induce myoclonus.

Methods

We performed a chart review of 3 patients with myoclonus secondary to ciprofloxacin and reviewed the literature for similar cases. Written consent for publication was obtained from each patient, and their identities were concealed for ethical reasons.

Results

We describe 3 cases of myoclonus secondary to ciprofloxacin, 2 males and a female aged 61, 26, and 48 years, respectively. The myoclonus appeared within 3 days of ciprofloxacin intake. In all 3 cases, ciprofloxacin was prescribed for urinary tract infection. Electroencephalogram and neuroimaging studies were normal and possible causes were excluded. Thus, ciprofloxacin was believed to be the underlying cause and hence it was withdrawn. The patients had complete recovery on follow-up.

Conclusions

Although ciprofloxacin is widely prescribed for different infections, only 13 cases were reported to develop myoclonus secondary to ciprofloxacin. The mean age of patients was 62 years. Fifty-four percent of cases were males. Cessation of ciprofloxacin was the most common management course. All individuals fully recovered after ciprofloxacin withdrawal. The mechanism of ciprofloxacin-induced myoclonus is probably associated with γ-aminobutyric acid and glutamate pathways.
Differences in the sequence analysis sequence analysis of pMGA 1.2 and pMGA 1.3 among isolated field strains of Mycoplasma gallisepticum that produce deformed eggs in laying hens.
Authors: Maya-Rodríguez Linda , Gómez-Verduzco Gabriela , Trigo-Tavera Francisco J. , Moreno-Fierros Leticia , Miranda-Morales Rosa Elena
Published: August 2023

Mycoplasmosis in poultry is a chronical disease that causes economical losses in farming, and it is difficult to eradicate in flocks. Mycoplasma gallisepticum (MG) is one agent of this disease, this bacterium has many important superficial proteins to get infection, working as adhesin, transporter and evasion of immune system. The adhesin lipoprotein designed as pMGA has this function, present variability antigenic and it is conformed for 9 regions being the sequences pMGA1.2 and pMGA1.3 which have a 97% identity of amino acid conformation, for this reason they could be stables segments. The aim of this study was to determine the differences and similar regions in field strains through M83178.1 sequence. From 18 field strains collected (16 form egg, 1 oviduct and 1 air sac) of laying hen flocks. The 18 strains typified as Myc. gallisepticum by PCR with mgc2 gene. There were performed 6 internal primers to cover all sequences, while MGS6 and MSWUV1853 strains were used as positive and negative controls respectively. The results showed more frequently amplification close to the C-terminal region, but interesting no field strain presented the same amplification region as MGS6. The bioinformatic analysis was made for internal segments 4 and 6 only, analysis shows cluster affinity at sequence 6, when the sequences were translated to amino acids through MEGA program, they were compatible with conserved sequences in Myco_haema proteins domains in the genus Mycoplasma that belong to Q7NAP3_MYCGA VlhA.3.04. Differences in the sequence analysis of the field strain were demonstrated, but at the same time was identified a homologue region protein domain what can indicate a genetic transference as consequence of bacteria evolution. The outcomes showed the dynamic variability in pMGA protein, whose difference could represent an important factor for the development for vaccines to provide protection against Myc. gallisepticum infection in chickens.
Results of the 2020 Genomic Proficiency Test for the network of European Union Reference Laboratory for Antimicrobial Resistance assessing whole-genome-sequencing capacities
Authors: Kristensen Thea , Sørensen Lauge Holm , Pedersen Susanne Karlsmose , Jensen Jacob Dyring , Mordhorst Hanne , Lacy-Roberts Niamh , Lukjancenko Oksana , Luo Yan , Hoffmann Maria , Hendriksen Rene S.
Published: August 2023

The global surveillance and outbreak investigation of antimicrobial resistance (AMR) is amidst a paradigm shift from traditional biology to bioinformatics. This is due to developments in whole-genome-sequencing (WGS) technologies, bioinformatics tools, and reduced costs. The increased use of WGS is accompanied by challenges such as standardization, quality control (QC), and data sharing. Thus, there is global need for inter-laboratory WGS proficiency test (PT) schemes to evaluate laboratories' capacity to produce reliable genomic data. Here, we present the results of the first iteration of the Genomic PT (GPT) organized by the Global Capacity Building Group at the Technical University of Denmark in 2020. Participating laboratories sequenced two isolates and corresponding DNA of

Salmonella enterica

,

Escherichia coli

and

Campylobacter coli

, using WGS methodologies routinely employed at their laboratories. The participants' ability to obtain consistently good-quality WGS data was assessed based on several QC WGS metrics. A total of 21 laboratories from 21 European countries submitted WGS and meta-data. Most delivered high-quality sequence data with only two laboratories identified as overall underperforming. The QC metrics, N50 and number of contigs, were identified as good indicators for high-sequencing quality. We propose QC thresholds for N50 greater than 20 000 and 25 000 for

Campylobacter coli

and Escherichia coli, respectively, and number of contigs >200 bp greater than 225, 265 and 100 for

Salmonella enterica

,

Escherichia coli

and

Campylobacter coli

, respectively. The GPT2020 results confirm the importance of systematic QC procedures, ensuring the submission of reliable WGS data for surveillance and outbreak investigation to meet the requirements of the paradigm shift in methodology.
SomaticTET2Mutations are Associated with Giant Cell Arteritis
Authors: Robinette Michelle L. , Weeks Lachelle D. , Kramer Ryan J. , Agrawal Mridul , Gibson Christopher J. , Yu Zhi , Sekar Aswin , Mehta Arnav , Niroula Abhishek , Brown Jared T. , McDermott Gregory C. , Reshef Edith R. , Lu Jonathan E , Liou Victor D. , Chiou Carolina A. , Natarajan Pradeep , Freitag Suzanne K. , Rao Deepak A. , Ebert Benjamin L.
Published: August 2023

Objective

Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HM). How the presence of somatic mutations which drive development of HM, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood.

Methods

To examine an association between CH and GCA, we analyzed sequenced exomes of 470960 UK Biobank participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations.

Results

UKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (HR 2.98, p =0.00178) and withTET2mutation (HR 2.02, p =0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, 3 of whom had HM at GCA diagnosis.TET2mutations were associated with vision loss in patients with GCA (OR 4.33, p = 0.047).

Conclusions

CH increases risk for development of GCA in a genotype-specific fashion, with greatest risk being conferred by the presence of mutations inTET2. SomaticTET2mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.
How group structure impacts the numbers at risk for coronary artery disease: polygenic risk scores and non-genetic risk factors in the UK Biobank cohort
Authors: Zhao Jinbo , O’Hagan Adrian , Salter-Townshend Michael
Published: August 2023

The UK Biobank is a large cohort study that recruited over 500,000 British participants aged 40-69 in 2006-2010 at 22 assessment centres from across the UK. Self-reported health outcomes and hospital admission data are two types of records that include participants’ disease status. Coronary artery disease (CAD) is the most common cause of death in the UK Biobank cohort. After distinguishing between prevalence and incidence CAD events for all UK Biobank participants, we identified geographical variations in age-standardised rates of CAD between assessment centres. Significant distributional differences were found between the pooled cohort equation scores of UK Biobank participants from England and Scotland using the Mann-Whitney test. Polygenic risk scores of UK Biobank participants from England and Scotland and from different assessment centres differed significantly using permutation tests. Our aim was to discriminate between assessment centres with different disease rates by collecting data on disease-related risk factors. However, relying solely on individual-level predictions and averaging them to obtain group-level predictions proved ineffective, particularly due to the presence of correlated covariates resulting from participation bias. By using the Mundlak model, which estimates a random effects regression by including the group means of the independent variables in the model, we effectively addressed these issues. In addition, we designed a simulation experiment to demonstrate the functionality of the Mundlak model. Our findings have applications in public health funding and strategy, as our approach can be used to predict case rates in the future, as both population structure and lifestyle changes are uncertain.
The MidPIC study: Midwives’ knowledge, perspectives and learning needs regarding preconception and interconception care
Authors: Bradfield Zoe , Leefhelm Emily , Soh Sze-Ee , Black Kirsten I , Boyle Jaqueline A , Kuliukas Lesley , Harrison Cheryce , Homer Caroline SE , Smith Rachel M , Skouteris Helen
Published: August 2023

Background

Preconception and interconception care improves the health outcomes of women and communities.

Problem

Little is known about how prepared and willing Australian midwives are to provide preconception and interconception care.

Aim

The aim of this study was to explore midwives’ knowledge, perspectives and learning needs, and barriers and enablers to delivering preconception and interconception care.

Methods

We conducted a cross-sectional exploratory study of midwives working in any Australian maternity setting. An online survey was administered that included items measuring midwives’ self-rated knowledge; education needs and preferences; attitudes and perceptions towards the pre and interconception care; and views on future service and workforce planning.

Quantitative data were analysed descriptively, and demographic characteristics (e.g., years of experience, model of care) associated with knowledge and attitudes regarding pre- and inter-conception care were examined using univariate logistic regression analysis. Qualitative data were captured through open-ended questions and analysed using inductive content analysis.

Findings

We collected responses from (n=338) out of 355 midwives who were eligible for this study working across all Australian models of care (completion rate 96%). Most participants (n=290; 85%) rated their overall knowledge about pre and interconception health for women as excellent, above average or average. The only variable associated with overall knowledge was years of experience, with participants more than 11 years of experience more likely to report above average to excellent knowledge (OR 3.11; 95% CI 1.09, 8.85). The majority (n=257; 76%) were interested in providing pre and interconception care more regularly within their role. Low prioritisation in service planning/budgeting was the most frequently selected barrier to providing preconception and interconception care.

Implications

Findings revealed that midwives are prepared and willing to provide preconception and interconception care. Pre and post registration professional development; service and funding reform; and policy development are critical to enable Australian midwives’ provision of pre and interconception care.
The Role of C-to-U RNA Editing in Human Biodiversity
Authors: Van Norden Melissa , Falls Zackary , Mandloi Sapan , Segal Brahm , Baysal Bora , Samudrala Ram , Elkin Peter L.
Published: August 2023

Intra-organism biodiversity is thought to arise from epigenetic modification of our constituent genes and post-translational modifications after mRNA is translated into proteins. We have found that post-transcriptional modification, also known as RNA editing, is also responsible for a significant amount of our biodiversity, substantively expanding this story. The APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family RNA editing enzymes APOBEC3A and APOBEC3G catalyze the deamination of cytosines to uracils (C>U) in specific stem-loop structures.1,2We used RNAsee (RNA site editing evaluation), a tool developed to predict the locations of APOBEC3A/G RNA editing sites, to determine whether known single nucleotide polymorphisms (SNPs) in DNA could be replicated in RNA via RNA editing. About 4.5% of non-synonymous SNPs which result in C>U changes in RNA, and about 5.4% of such SNPs labelled as pathogenic, were identified as probable sites for APOBEC3A/G editing. This suggests that the variant proteins created by these DNA mutations may also be created by transient RNA editing, with the potential to affect human health. Those SNPs identified as potential APOBEC3A/G-mediated RNA editing sites were disproportionately associated with cardiovascular diseases, digestive system diseases, and musculoskeletal diseases. Future work should focus on common sites of RNA editing, any variant proteins created by these RNA editing sites, and the effects of these variants on protein diversity and human health. Classically, our biodiversity is thought to come from our constitutive genetics, epigenetic phenomenon, transcriptional differences, and post-translational modification of proteins. Here, we have shown evidence that RNA editing, often stimulated by environmental factors, could account for a significant degree of the protein biodiversity leading to human disease. In an era where worries about our changing environment are ever increasing, from the warming of our climate to the emergence of new diseases to the infiltration of microplastics and pollutants into our bodies, understanding how environmentally sensitive mechanisms like RNA editing affect our own cells is essential.
Klebsiella pneumoniaeOmpR facilitates lung infection through transcriptional regulation of key virulence factors
Authors: Janssen Axel B. , de Bakker Vincent , Aprianto Rieza , Trebosc Vincent , Kemmer Christian , Pieren Michel , Veening Jan-Willem
Published: August 2023

Bacteria must adapt to the stresses of specific environmental conditions to survive. This adaptation is often achieved by altering gene expression through two-component regulatory systems (TCSs). In Gram-negative bacteria, the response to environmental changes in osmolarity and pH are primarily mediated by the EnvZ/OmpR TCS. Although the functioning of EnvZ/OmpR has been well characterized inEscherichia coli,Salmonella enterica, and theYersiniagenus, the importance of EnvZ/OmpR TCS in the opportunistic human pathogenKlebsiella pneumoniaehas been limitedly studied.

Here, we investigated the importance of EnvZ/OmpR inK. pneumoniaefor fitness, gene regulation, virulence, and infection. Through the generation of a markerlessompR-deletion mutant, we show that overall fitness ofK. pneumoniaeis not impactedin vitro. Using dual RNA-seq ofK. pneumoniaeco-incubated with human lung epithelial cells we demonstrate that theK. pneumoniaeOmpR regulon includes important virulence factors, but shows otherwise limited overlap with the regulons of other Gram-negative bacteria. In addition, we show that deletion ofompRinK. pneumoniaeleads to a stronger antibacterial transcriptional response in human lung epithelial cells. Lastly, we show that OmpR is crucial forK. pneumoniaevirulence and infection through a murine lung infection model.

As the adaptation of commensal bacteria to specific niches is mediated by TCSs, we show that EnvZ/OmpR plays a crucial role in successful lung infection, as well as in virulence. These results suggest that OmpR is an interesting target for anti-virulence drug discovery programs.

Importance

Bacteria use two-component regulatory systems (TCSs) to adapt to changes in their environment by changing their gene expression. In this study, we show that the EnvZ/OmpR TCS ofKlebsiella pneumoniaeplays an important role in successfully establishing lung infection, and virulence. In addition, we discern the transcriptional response that OmpR facilitates within this clinically relevant opportunistic pathogen, and within the host. This work suggests thatK. pneumoniaeOmpR might be a promising target for innovative anti-infectives.
A cell-autonomous mechanism regulates BCAA catabolism in white adipocytes and systemic metabolic balance
Authors: Aguillard Ashley M. , Tzeng Joyce , Ferrer Ismael , Tam Bjorn T. , Lorenzo Damaris N.
Published: August 2023

Elevated plasma branched-chain amino acids (BCAAs) are strongly associated with obesity, insulin resistance (IR), and diabetes in humans and rodent models. However, the mechanisms of BCAA dysregulation and its systemic, organ, and cell-specific implications in the development of obesity and IR are not well understood. To gain mechanistic insight into the causes and effects of plasma BCAA elevations, we leveraged mouse models with high circulating BCAA levels prior to the onset of obesity and IR. Young mice lacking ankyrin-B in white adipose tissue (WAT) or bearing an ankyrin-B variant that causes age-driven metabolic syndrome exhibit downregulation of BCAA catabolism selectively in WAT and excess plasma BCAAs. Using cellular assays, we demonstrated that ankyrin-B promotes the surface localization of the amino acid transporter Asct2 in white adipocytes, and its deficit impairs BCAA uptake. Excess BCAA supplementation worsened glucose tolerance and insulin sensitivity across genotypes. In contrast, BCAA overconsumption only increased adiposity in control mice, implicating WAT utilization of BCAAs in their obesogenic effects. These results shed light into the mechanistic underpinnings of metabolic syndrome caused by ankyrin-B deficits and provide new evidence of the relevance of WAT in the regulation of systemic BCAA levels, adiposity, and glucose homeostasis.

ARTICLE HIGHLIGHTS

Ankyrin-B deficits in adipose tissue result in elevated circulating BCAAs before the onset of obesity and insulin resistance.

Ankyrin-B promotes the surface localization of the amino acid transporter Asct2 in white adipocytes and BCAA uptake.

Excess BCAA supplementation worsens glucose tolerance and insulin sensitivity in ankyrin-B deficient mice.

BCAA utilization by white adipose tissue is required for the obesogenic effects of BCAA overconsumption.
Oryzagenera-specific novel Histone H4 variant predisposes H4 Lysine5 Acetylation marks to modulate salt stress responses
Authors: Vivek Hari Sundar G , Sotelo-Parrilla Paula , Raju Steffi , Jha Shaileshanand , Gireesh Anjitha , Gut Fabian , Vinothkumar K.R. , Berger Frédéric , Jeyaprakash A. Arockia , Shivaprasad P.V.
Published: August 2023

Paralogous variants of canonical histones guide accessibility to DNA and function as additional layers of genome regulation. Across eukaryotes, the occurrence, mechanism of action and functional significance of several variants of core histones are well known except that of histone H4. Here we show that a novel variant of H4 (H4.V), expressing tissue-specifically among members ofOryzagenera, mediates specific epigenetic changes contributing majorly to salt tolerance. H4.V was incorporated to specific chromosomal locations where it blocked deposition of active histone marks. Under salt stress, large scale re-distribution of H4.V enabled incorporation of stress dependent histone H4 Lysine5 Acetylation (H4K5Ac) marks. Mis-expression of H4.V led to defects at morphological level especially in reproductive tissues, and in mounting stress responses. H4.V mediated these alterations by condensing chromatin at specific genomic regions as seen with cryo-EM structure of reconstituted H4.V containing nucleosomes. These results not only uncovered the presence of a H4 variant in plants, but also a novel chromatin regulation of stress responses that might have contributed to success of semi-aquaticOryzamembers under variable water-limiting conditions.

One-line summary

Histone H4 variant predisposes chromatin for stress responses

Abstract Figure
Immunities Specific to Both of the M Protein Ectodomain and RBD Synergize to Confer Cross-protection against SARS-CoV-2 Infections
Authors: Tang Yibo , Tang Kaiming , Hu Yunqi , Ye Zi-Wei , Luo Wanyu , Luo Cuiting , Cao Hehe , Wang Ran , Liu Dejian , Liu Cuicui , Ge Xingyi , Chen Yaoqing , Yuan Shuofeng , Deng Lei
Published: August 2023

The effectiveness of the prototypic SARS-CoV-2 vaccine largely decreased overtime against the emerging virus strains, necessitating the universal vaccine development. The most abundant structural membrane (M) protein is highly conserved in amino acid sequence, which arouses our research interests in developing a universal immunogen based on it. Serological analysis showed that IgG responses specific to its N-terminal peptides can be strongly detected in many serum samples from both convalescent patients and vaccinees receiving inactivated vaccines, indicating the potential existence of human B-cell epitopes in reactive peptides. Microneutralization assays showed that the N-terminal peptide S2M2-30-specific hyperimmune serum was capable of cross-neutralizing the authentic viruses including wild-type HKU-001a, B.1.617.2/Delta, and Omicron subvariant BQ.1.1, and synergized with RBD-specific serum in reinforcing antiviral activities. Strong S2M2-30-specific immunities elicited in hACE2-transgenic mice could effectively inhibit B.1.1.7/Alpha (UK) infections. Our results suggest the potentiality of conserved M peptides as vaccine targets for conferring cross-protections against sarbecoviruses.
An essential protease, FtsH, influences daptomycin resistance acquisition inEnterococcus faecalis
Authors: Nair Zeus Jaren , Gao Iris Hanxing , Firras Aslam , Chong Kelvin Kian Long , Choo Pei Yi , Pethe Kevin , Kline Kimberly A.
Published: August 2023

Daptomycin is a last-line antibiotic commonly used to treat vancomycin resistant Enterococci, but resistance evolves rapidly and further restricts already limited treatment options. While genetic determinants associated with clinical daptomycin resistance (DAPR) have been described, information on factors affecting the speed of DAPRacquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol modifying enzyme involved in cationic antimicrobial resistance, is linked to DAPRin pathogens such as methicillin-resistantStaphylococcus aureus. SinceEnterococcus faecalisencodes two paralogs ofmprFand clinical DAPRmutations do not map tomprF,we hypothesized that functional redundancy between the paralogs preventsmprF-mediated resistance and masks other evolutionary pathways to DAPR. Here we performedin vitroevolution to DAPRinmprFmutant background. We discovered that the absence ofmprFresults in slowed DAPRevolution and is associated with inactivating mutations inftsHresulting in the depletion of the chaperone repressor HrcA. We also report thatftsHis essential in the parental, but not in the ΔmprF, strain where FtsH depletion results in growth impairment in the parental strain, a phenotype associated with reduced glycolysis and reduced ability for metabolic reduction. This presents FtsH and HrcA as enticing targets for developing anti-resistance strategies.

Graphical Abstract
Loss of PAX6 alters the excitatory/inhibitory neuronal ratio in human cerebral organoids
Authors: Chan Wai Kit , Negro Danilo , Munro Victoria M , Marshall Helen , Kozić Zrinko , Brown Megan , Beltran Mariana , Henderson Neil C , Price David J , Mason John O
Published: August 2023

The transcription factor PAX6 is a crucial regulator of multiple aspects of embryonic forebrain development. Its well-known roles in mice include regulating differentiation of excitatory and inhibitory neurons in the embryonic cortex. PAX6’s roles during human forebrain development are less well understood. Using human cerebral organoids, we investigated PAX6’s roles in human neurodevelopment. Homozygous PAX6 mutant (PAX6-/-) organoids were larger than controls and contained inhibitory cell types not found inPAX6+/+controls. These inhibitory cells exhibited clear transcriptomic similarities and comparable distribution to analogous inhibitory cells previously described inPax6-/-mice. Differentiation trajectory inferencing showed that the inhibitory cells were generated from both radial glia and neuroectodermal progenitor populations. Inferring cell-cell communication using CellChat showed that loss of PAX6 in cerebral organoids increased the probability of cells engaging with inappropriate signalling pathways. Our findings indicate that while PAX6’s role in controlling excitatory versus inhibitory neural differentiation is conserved, there are alterations in the activities of intercellular signalling pathways in humanPAX6-/-cortical progenitors that have not been described in mice, indicating potential species-specific mechanistic differences.

Summary Statement

To identify likely roles of PAX6 during human embryonic development, we generated and analysed human PAX6 mutant cerebral organoids, revealing strong similarities and some differences to Pax6’s well-known roles in rodents.