Pregnancy Outcomes in Women With Rheumatoid Arthritis: A Systematic Review and Meta-analysis.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease affecting multiple joints and can also be a systemic widespread, affecting major organs. Rheumatoid arthritis is associated with greater adverse maternal and neonatal outcomes in comparison to the general obstetric population. This systematic review and meta-analysis aims to investigate the pregnancy outcomes in RA patients in comparison to the general pregnant population.Nine studies involving 11,999 RA patients met the eligibility criteria with 9,921,808 controls. Rheumatoid arthritis patients were compared with their control counterparts according to random-effects model statistical analysis.We searched databases from inception to September 8, 2021. Eligible studies reported maternal outcomes (preeclampsia, cesarean delivery, and preterm delivery) and/or neonatal outcomes. Data were pooled across using random-effects model. Subgroup analysis was conducted on RA patients alone. The review was registered prospectively with PROSPERO (CRD42021250521).In terms of maternal outcomes, there was an increased rate of cesarean delivery (odds ratio [OR], 1.55), preeclampsia (OR, 1.61), and preterm delivery (OR, 1.83) in RA patients compared with their control counterparts. In terms of neonatal outcomes, a higher rate of lower gestational weight (mean difference [MD], -0.19 kg), requirement for neonate intensive care unit admission (OR, 1.34), and stillbirths (OR, 1.99) were observed in RA patients compared with the controls. A subgroup analysis of 4 studies involving only RA patients (n = 3761) was conducted. A total of 33.2% of patients had a cesarean delivery, 7.3% had preeclampsia, 14.8% had a preterm delivery, and 9.5% of neonates had low birth weight.Compared with the general pregnant population, women with RA tend to have a higher risk of maternal and neonatal complications. As a result, this study hopes to increase awareness into the importance of counseling and managing RA patients.

Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS.

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.

Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles.

Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity.

Antimicrobial resistance to ceftazidime involving loss of penicillin-binding protein 3 in Burkholderia pseudomallei.

Known mechanisms of resistance to ß-lactam antibiotics include ß-lactamase expression, altered drug target, decreased bacterial permeability, and increased drug efflux. Here, we describe a unique mechanism of ß-lactam resistance in the biothreat organism Burkholderia pseudomallei (the cause of melioidosis), associated with treatment failure during prolonged ceftazidime therapy of natural infection. Detailed comparisons of the initial ceftazidime-susceptible infecting isolate and subsequent ceftazidime-resistant variants from six patients led us to identify a common, large-scale genomic loss involving a minimum of 49 genes in all six resistant strains. Mutational analysis of wild-type B. pseudomallei demonstrated that ceftazidime resistance was due to deletion of a gene encoding a penicillin-binding protein 3 (BPSS1219) present within the region of genomic loss. The clinical ceftazidime-resistant variants failed to grow using commonly used laboratory culture media, including commercial blood cultures, rendering the variants almost undetectable in the diagnostic laboratory. Melioidosis is notoriously difficult to cure and clinical treatment failure is common in patients treated with ceftazidime, the drug of first choice across most of Southeast Asia where the majority of cases are reported. The mechanism described here represents an explanation for ceftazidime treatment failure, and may be a frequent but undetected resistance event.

Examining the Characteristics of Colchicine-Induced Myelosuppression in Clinical Cases: A Systematic Review.

OBJECTIVE: The use of colchicine has been associated with varying degrees of myelosuppression. Despite expanded use in cardiovascular and inflammatory conditions, there remains clinician concern because of potential myelosuppressive side effects. A systematic review was conducted to explore the reported myelosuppressive events of colchicine. METHODS: A systematic review was conducted using the MeSH terms ("colchicine") AND ("myelosuppression," "bone*," "marrow," "suppression," "aplasia," "leukopenia/leucopenia," "lymphopenia," "neutropenia") on September 1, 2020, and was updated on November 30, 2021. The search was conducted in PubMed, ScienceDirect, Scopus, Embase, and Cochrane Library. The search included references published from 1978 to 2020 and was limited to English-language observational studies (ie, case reports, case series, case control studies, and cohort studies) or trial data. RESULTS: In total, 3233 articles were screened, with 30 studies of 47 patients with myelosuppression from colchicine identified. Most patients with myelosuppression had comorbidities, including renal impairment (21/47, 44.7%). Out of 47 patients, 15 (31.9%) and 13 (27.7%) were reported to be concurrently taking cytochrome P450 3A4 (CYP3A4) inhibitors and P-glycoprotein (P-gp) efflux transporter inhibitors, respectively. Patients with renal impairment accounted for the majority of overall patients taking these CYP3A4 and P-gp inhibitors (8/15, 53.3%, and 8/13, 61.5%, respectively). Out of 21 patients with renal impairment, 13 had worsening cytopenia during colchicine use. The presentations ranged from moderate anemia (grade 2) to severe thrombocytopenia, neutropenia, and leukopenia (grade 4). CONCLUSION: Colchicine has few reports of myelosuppression. The majority of patients with myelosuppression had preexisting renal impairment or concomitant CYP3A4 or P-gp inhibitor use. Caution should be taken in this subset of patients with increased monitoring.

Open versus laparoscopic surgery in the management of patients with gallbladder cancer: A systematic review and meta-analysis.

BACKGROUND: The aim of this meta-analysis was to assess the safety and efficacy of laparoscopic surgery when compared to open surgery in the management of gallbladder cancer. METHODS: Ovid Cochrane Library, Medline, Embase, Epub, and Scopus were searched. A meta-analysis of selected studies was performed, and a subgroup analysis was performed by tumor stage. RESULTS: Fourteen studies met the eligibility criteria with a total of 1792 participants undergoing either laparoscopic or open surgery. Survival rate of laparoscopic group was higher than open group at T2 tumor stage after 1 year (OR = 2.130, 95%CI: 1.372, 3.306, I2 = 0%) and 2 year (OR = 2.074, 95%CI: 1.411, 3.050, I2 = 0%) as well as T3 tumor stage after 1 year (OR = 2.805, 95%CI: 1.631, 4.826, I2 = 0%) and 2 year (OR = 2.453, 95%CI: 1.367, 4.400, I2 = 0%). Additionally, overall recurrence rate between laparoscopic and open cohorts was similar (OR: 1.098, 95%CI: 0.774, 1.558, I2 = 5.56%). CONCLUSION: In comparison to open surgery, the results seem to show a trend favoring laparoscopic surgery as a possible alternative treatment option to commence the management of gallbladder cancer.

Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: a systematic review and meta-analysis.

AstraZeneca coronavirus disease 2019 (COVID-19) vaccinations have recently been implicated in thromboembolism formations. Our aim was to investigate the outcomes of patients with thromboembolic events following the AstraZeneca vaccine (ChAdOx1 nCoV-19, AZD1222). A literature search was performed from December 2019 to September 2021. Eligible studies must report participants older than 18 years vaccinated with AstraZeneca and outcomes of thromboembolic events. Pooled mean or proportion were analyzed using a random-effects model. A total of 45 unique studies (number of patients = 144, 64.6% women, mean age 21-68 years) were included. The most common presenting adverse events were headache (12.1%), intracerebral hemorrhage (7.5%), and hemiparesis (7%). The most common thromboembolic adverse events were cerebral venous sinus thrombosis (38.5%) and deep vein thrombosis/pulmonary embolism (21.1%). The most common radiologic finding were intracerebral hemorrhage and cerebral venous thrombosis. Laboratory findings included thrombocytopenia (75%) and hypofibrinogenemia (41%). On admission, 64 patients tested positive for PF4-Heparin ELISA assay (80%). Seventy-four patients were hospitalized with 22 being admitted to the ICU. A total of 78 patients recovered while 39 patients died. This meta-analysis presents evidence to suggest vaccine-induced immune thrombotic thrombocytopenia (VITT) following AstraZeneca vaccine. Clinical practice must, therefore, account for the possibility of VITT and subsequent embolic events in certain individuals' postvaccination with adenovirus-based COVID-19 vaccines. Serum anti-PF4 suggests diagnostic value for VITT and could subsequently inform treatment choices in such instances.

pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model.

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by mutant huntingtin (mHTT). Phosphorylation at serine-421 (pS421) of mHTT has been shown to be neuroprotective in cellular and rodent models. However, the genetic context of these models differs from that of HD patients. Here we employed human pluripotent stem cells (hiPSCs), which express endogenous full-length mHTT. Using genome editing, we generated isogenic hiPSC lines in which the S421 site in mHTT has been mutated into a phospho-mimetic aspartic acid (S421D) or phospho-resistant alanine (S421A). We observed that S421D, rather than S421A, confers neuroprotection in hiPSC-derived neural cells. Although we observed no effect of S421D on mHTT clearance or axonal transport, two aspects previously reported to be impacted by phosphorylation of mHTT at S421, our analysis revealed modulation of several aspects of mitochondrial form and function. These include mitochondrial surface area, volume, and counts, as well as improved mitochondrial membrane potential and oxidative phosphorylation. Our study validates the protective role of pS421 on mHTT and highlights a facet of the relationship between mHTT and mitochondrial changes in the context of human physiology with potential relevance to the pathogenesis of HD.

Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome.

BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or nonisogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal properties in the context of isogenic human neurons remains lacking. METHODS: Using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 to introduce indels in exon 3 of FMR1, we generated an isogenic human pluripotent stem cell model of FXS that shows complete loss of FMRP expression. We generated neuronal cultures and performed genome-wide transcriptome and proteome profiling followed by functional validation of key dysregulated processes. We further analyzed neurodevelopmental and neuronal properties, including neurite length and neuronal activity, using multielectrode arrays and patch clamp electrophysiology. RESULTS: We showed that the transcriptome and proteome profiles of isogenic FMRP-deficient neurons demonstrate perturbations in synaptic transmission, neuron differentiation, cell proliferation and ion transmembrane transporter activity pathways, and autism spectrum disorder-associated gene sets. We uncovered key deficits in FMRP-deficient cells demonstrating abnormal neural rosette formation and neural progenitor cell proliferation. We further showed that FMRP-deficient neurons exhibit a number of additional phenotypic abnormalities, including neurite outgrowth and branching deficits and impaired electrophysiological network activity. These FMRP-deficient related impairments have also been validated in additional FXS patient-derived human-induced pluripotent stem cell neural cells. CONCLUSIONS: Using isogenic human pluripotent stem cells as a model to investigate the pathophysiology of FXS in human neurons, we reveal key neural abnormalities arising from the loss of FMRP.

Unbiased Profiling of Isogenic Huntington Disease hPSC-Derived CNS and Peripheral Cells Reveals Strong Cell-Type Specificity of CAG Length Effects.

In Huntington disease (HD), the analysis of tissue-specific CAG repeat length effects has been challenging, given the difficulty in obtaining relevant patient tissues with a broad range of CAG repeat lengths. We used genome editing to generate an allelic panel of isogenic HD (IsoHD) human embryonic stem cell (hESC) lines carrying varying CAG repeat lengths in the first exon of HTT. Functional analyses in differentiated neural cells revealed CAG repeat length-related abnormalities in mitochondrial respiration and oxidative stress and enhanced susceptibility to DNA damage. To explore tissue-specific effects in HD, we differentiated the IsoHD panel into neural progenitor cells, neurons, hepatocytes, and muscle cells. Transcriptomic and proteomic analyses of the resultant cell types identified CAG repeat length-dependent and cell-type-specific molecular phenotypes. We anticipate that the IsoHD panel and transcriptomic and proteomic data will serve as a versatile, open-access platform to dissect the molecular factors contributing to HD pathogenesis.

Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells.

Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs.

Genomic acquisition of a capsular polysaccharide virulence cluster by non-pathogenic Burkholderia isolates.

BACKGROUND: Burkholderia thailandensis is a non-pathogenic environmental saprophyte closely related to Burkholderia pseudomallei, the causative agent of the often fatal animal and human disease melioidosis. To study B. thailandensis genomic variation, we profiled 50 isolates using a pan-genome microarray comprising genomic elements from 28 Burkholderia strains and species. RESULTS: Of 39 genomic regions variably present across the B. thailandensis strains, 13 regions corresponded to known genomic islands, while 26 regions were novel. Variant B. thailandensis isolates exhibited isolated acquisition of a capsular polysaccharide biosynthesis gene cluster (B. pseudomallei-like capsular polysaccharide) closely resembling a similar cluster in B. pseudomallei that is essential for virulence in mammals; presence of this cluster was confirmed by whole genome sequencing of a representative variant strain (B. thailandensis E555). Both whole-genome microarray and multi-locus sequence typing analysis revealed that the variant strains formed part of a phylogenetic subgroup distinct from the ancestral B. thailandensis population and were associated with atypical isolation sources when compared to the majority of previously described B. thailandensis strains. In functional assays, B. thailandensis E555 exhibited several B. pseudomallei-like phenotypes, including colony wrinkling, resistance to human complement binding, and intracellular macrophage survival. However, in murine infection assays, B. thailandensis E555 did not exhibit enhanced virulence relative to other B. thailandensis strains, suggesting that additional factors are required to successfully colonize and infect mammals. CONCLUSIONS: The discovery of such novel variant strains demonstrates how unbiased genomic surveys of non-pathogenic isolates can reveal insights into the development and emergence of new pathogenic species.