Risk of rituximab-induced hepatitis B flare after antiviral discontinuation in rheumatic patients with chronic hepatitis B virus.

OBJECTVES: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents. METHODS: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed. RESULTS: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate. CONCLUSIONS: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

COVID-19 Infection Percentage Estimation from Computed Tomography Scans: Results and Insights from the International Per-COVID-19 Challenge.

COVID-19 analysis from medical imaging is an important task that has been intensively studied in the last years due to the spread of the COVID-19 pandemic. In fact, medical imaging has often been used as a complementary or main tool to recognize the infected persons. On the other hand, medical imaging has the ability to provide more details about COVID-19 infection, including its severity and spread, which makes it possible to evaluate the infection and follow-up the patient's state. CT scans are the most informative tool for COVID-19 infection, where the evaluation of COVID-19 infection is usually performed through infection segmentation. However, segmentation is a tedious task that requires much effort and time from expert radiologists. To deal with this limitation, an efficient framework for estimating COVID-19 infection as a regression task is proposed. The goal of the Per-COVID-19 challenge is to test the efficiency of modern deep learning methods on COVID-19 infection percentage estimation (CIPE) from CT scans. Participants had to develop an efficient deep learning approach that can learn from noisy data. In addition, participants had to cope with many challenges, including those related to COVID-19 infection complexity and crossdataset scenarios. This paper provides an overview of the COVID-19 infection percentage estimation challenge (Per-COVID-19) held at MIA-COVID-2022. Details of the competition data, challenges, and evaluation metrics are presented. The best performing approaches and their results are described and discussed.

Cone-beam x-ray luminescence computed tomography (CB-XLCT) prototype development and performance evaluation.

This study developed a prototype for a rotational cone-beam x-ray luminescence computed tomography (CB-XLCT) system, considering its potential application in pre-clinical theranostic imaging. A geometric calibration method applicable to both imaging chains (XL and CT) was also developed to enhance image quality. The results of systematic performance evaluations were presented to assess the feasibility of commercializing XLCT technology. Monte Carlo GATE simulation was performed to determine the optimal imaging conditions for nanophosphor particles (NPs) irradiated by 70 kV x-rays. We acquired a low-dose transmission x-ray tube and designed a prone positioning platform and a rotating gantry, using mice as targets from commercial small animalµ-CT systems. We then employed the image cross-correlation (ICC) automatic geometric calibration method to calibrate XL and CT images. The performance of the system was evaluated through a series of phantom experiments with a linearity of 0.99, and the contrast-to-noise ratio (CNR) between hydroxyl-apatite (HA) and based epoxy resin is 19.5. The XL images of the CB-XLCT prototype achieved a Dice similarity coefficient (DICE) of 0.149 for a distance of 1 mm between the two light sources. Finally, the final XLCT imaging results were demonstrated using the Letter phantoms with NPs. In summary, the CB-XLCT prototype developed in this study showed the potential to achieve high-quality imaging with acceptable radiation doses for small animals. The performance of CT images was comparable to current commercial machines, while the XL images exhibited promising results in phantom imaging, but further efforts are needed for biomedical applications.

Effects of declines in personal mastery on self-perceived mobility, physical function, cognitive function, and depressive symptoms: a 6-year follow-up study from the Social Environment and Biomarkers of Aging Study.

OBJECTIVES: As the psychosocial competence, personal mastery helps individuals to cope with stressful life events, and this study aims to examine impacts of declines in personal mastery on healthy aging among community-dwelling middle-aged and older adults using a nationally representative cohort. METHODS: Data from 648 study participants in the Social Environment and Biomarkers of Aging Study (SEBAS) were retrieved for analysis. All participants were divided into four groups based on their baseline and changes of personal mastery (measured by the Pearlin mastery score) during the 6-year follow-up. Multivariate logistic regression models were adopted to examine associations between declines in personal mastery and indicators for healthy aging (declines in self-perceived mobility, physical function (activities of daily living (ADLs) and instrumental activities of daily living (IADLs)), cognitive function and depressive symptoms). RESULTS: After adjustments for demographics and comorbidities, those with declines in personal mastery were associated with greater risks of declines in self-perceived mobility (adjusted odds ratio (aOR) 1.50 [95% confidence interval 1.01-2.22], p < 0.05). Although the point estimate in the unadjusted models indicated similar associations between declines in personal mastery and declines in ADLs, IADLs, cognitive function or depressive symptoms, these outcomes did not reach statistical significance in the adjusted model. CONCLUSIONS: Declines in personal mastery were negatively associated with indicators related to healthy aging (particularly locomotion) in a 6-year follow-up. Further investigations are needed to explore the effects of preventing declines in personal mastery in promoting healthy aging over time.

The Efficacy of Health Promotion Program Among Parents Who Had Children With Attention-Deficit/Hyperactivity-Disorder.

OBJECTIVES: To explore the effect of health promotion program (HPP) on stress, quality of life, health-promoting lifestyles, and children's attention-deficit/hyperactivity disorder (ADHD) symptoms in parents of children with ADHD. METHODS: Sixty parents of children with ADHD were equally randomized into the intervention (health promotion program) and control (usual care) groups. Outcomes included parents' stress, quality of life, health-promoting lifestyles, and children's ADHD symptoms before, immediately after, and 1, 3, and 6 months after the intervention. The GEE was used to evaluate the effectiveness. RESULTS: The intervention group reported significant improvement in the children's hyperactivity/impulse and opposition at the 6- and 3-month, respectively. Parental overall stress significantly improved at 3 and 6 months. Parents' quality of life had significant effects at the immediate, 3-month, and 6-month. Self-actualization behavior for health-promoting lifestyles had significant effects at the immediate follow-up. CONCLUSION: HPP can promote the mental well-being of parents of children with ADHD.

The significance of dense fine speckled pattern in antinuclear antibody-associated rheumatic disease and coexisting autoantibodies: A propensity score-matched cohort study.

AIM: To investigate the relationship between the prevalence of antinuclear antibody (ANA) -associated rheumatic diseases (AARD) and the presence of dense fine speckled (DFS) and homogeneous patterns in ANA tests. METHODS: This retrospective study enrolled adult patients with either a DFS or homogeneous pattern in their ANA test. A mixed pattern was defined as the presence of more than one pattern reported in the test. The presence of anti-DFS70 antibodies and other common autoantibodies were detected using EUROLINE ANA Profile 23. A 1:2 propensity score matching was applied to control for demographic and other interfering factors. RESULTS: A total of 59 patients with a DFS pattern were enrolled and compared with a matched homogeneous group. The DFS group had a significantly lower prevalence of AARD (3.4% vs. 16.9%, p = .008) and the subgroup with anti-DFS70 antibodies showed an even lower prevalence (2% vs. 20%, p = .002). Among the 33 patients with monospecific anti-DFS70 antibodies, five had a mixed pattern, and all patients with common autoantibodies had an isolated DFS pattern. CONCLUSIONS: The findings of this study suggest that patients with a DFS pattern in their ANA test may have a lower prevalence of AARD compared with those with a homogeneous pattern. However, an isolated DFS pattern in ANA testing does not necessarily indicate the presence of monospecific anti-DFS70 antibodies or AARD. Confirmatory testing for the monospecific anti-DFS70 antibody is mandatory to exclude AARD.

Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis.

Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA-anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article.

Unveiling the molecular basis of inflamm-aging induced by advanced glycation end products (AGEs)-modified human serum albumin (AGE-HSA) in patients with different immune-mediated diseases.

Increased serum advanced glycation end products (AGEs) are commonly found in the patients with Diabetes mellitus (DM), aging-related diseases, and immune-mediated diseases. These diseases are notorious for vasculopathy, immune dysfunctions, and low-grade inflammation mimicking inflamm-aging. However, the molecular basis of inflamm-aging related to AGEs remains elucidation. In this study, we incubated human serum albumin (HSA) and glucose at 37 °C in 5% CO2 incubator for 0-180 days to generate AGE-HSA. We found the mixture gradually changing the color from transparancy to brown color and increased molecular weight during incubation. The pH value also gradually decreased from 7.2 to 5.4 irrelevant to ionic charge or [Ca2+] concentration, but dependent on gradual glycation of the alkaline amino acids, lysine and arginine. Functionally, 40 µg/mL of AGE-HSA decreased IL-2 production from human Jurkat T cell line via suppressing p-STAT3, p-STAT4, and p-STAT6 with an increased tendency of senescence-associated ß-galactosidase (SA-ßgal) expression but irrelevant to change of Th1/Th2/Treg subpopulations. In contrast, AGE-HSA enhanced CC motif chemokine ligand 5 (CCL-5), IL-8, macrophage migration inhibitor factor (MIF), and interleukin 1 receptor antagonist (IL-1Ra) but suppressed SA-ßgal expression by human macrophage-like THP-1 cells. Interestingly, AGE-HSA abrogated the HSA-induced soluble intercellular adhesion molecules 1 (sICAM-1), sE-selectin and endothelin release from human coronary artery endothelial cells (HCAEC) and enhanced SA-ßgal expression. The accelerated and increased HSA glycations by individual inflammation-related cytokine such as IL-2, IL-6, IL-17, TGF-ß, or TNF-α in the in vitro study reflect increased serum AGE levels in patients with immune-mediated diseases. In conclusion, AGE-HSA can exert immunosuppresive, inflammatory and vasculopathic effects mimicking inflamm-aging in these patients.

2023 Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) Joint Consensus on Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. Objectives: This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. Methods: The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Conclusions: Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.

Quinazolinone-Peptido-Nitrophenyl-Derivatives as Potential Inhibitors of SARS-CoV-2 Main Protease.

The severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2-Mpro) plays an essential role in viral replication, transcription, maturation, and entry into host cells. Furthermore, its cleavage specificity for viruses, but not humans, makes it a promising drug target for the treatment of coronavirus disease 2019 (COVID-19). In this study, a fragment-based strategy including potential antiviral quinazolinone moiety and glutamine- or glutamate-derived peptidomimetic backbone and positioned nitro functional groups was used to synthesize putative Mpro inhibitors. Two compounds, G1 and G4, exhibited anti-Mpro enzymatic activity in a dose-dependent manner, with the calculated IC50 values of 22.47 ± 8.93 µM and 24.04 ± 0.67 µM, respectively. The bio-layer interferometer measured real-time binding. The dissociation kinetics of G1/Mpro and G4/Mpro also showed similar equilibrium dissociation constants (KD) of 2.60 × 10-5 M and 2.55 × 10-5 M, respectively, but exhibited distinct association/dissociation curves. Molecular docking of the two compounds revealed a similar binding cavity to the well-known Mpro inhibitor GC376, supporting a structure-function relationship. These findings may open a new avenue for developing new scaffolds for Mpro inhibition and advance anti-coronavirus drug research.

Characteristics and Potential Risk Factors of Hydroxychloroquine Retinopathy in Patients with Systemic Lupus Erythematosus: Focusing on Asian Population.

Purpose: Hydroxychloroquine (HCQ) would cause irreversible retinal damage, despite its pivotal role in treatment of systemic lupus erythematosus (SLE). This study aims to reassess the characteristics and risk factors of HCQ retinopathy. Methods: This study included patients with SLE who had used HCQ for >5 years and received ophthalmologic examinations during November 2017 to December 2020 in a tertiary hospital in Taiwan. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) were performed in all patients. Visual field assessment and/or multifocal electroretinography were done if suspicious findings were noted by SD-OCT or FAF. Clinical features and dosing details of HCQ were recorded by chart review. Results: Ninety-two patients were included, with the median duration of drug exposure of 11.2 years [interquartile range (IQR) 9.4-12.7 years], median daily dose of 6.9 mg/kg (IQR 6.1-7.7 mg/kg), and cumulative dose of 1,503.6 g (IQR 1,257.7-1,805.9 g). HCQ retinopathy was diagnosed in 10.9% of patients (10 of 92), and in 20.8% of patients (5 of 24) who complained about blurred vision. High myopia [odds ratio (OR) 5.03; 95% confidence interval (CI) 1.29-24.79; P = 0.03] and lower body weight (OR 0.88; 95% CI 0.78-0.97; P = 0.03) were significantly associated with HCQ retinopathy. Conclusions: Long-term HCQ users may suffer from retinal toxicity. Since there is no optimal substitute for HCQ, careful retinal evaluation is needed to avoid unnecessary drug discontinuation. In addition, an association between high myopia and HCQ retinopathy was noted. More investigation is needed to clarify this association.

Clinical features and prognostic predictors in patients with rheumatic diseases complicated by Pneumocystis pneumonia.

OBJECTIVES: To investigate the clinical outcomes and risk factors of mortality in patients with rheumatic diseases complicated by Pneumocystis pneumonia (PCP). METHODS: Between November 2015 and April 2021, patients with rheumatic diseases with PCP in a tertiary referral hospital were retrospectively enrolled. The diagnosis of PCP requires the fulfillment of clinical, radiographic, and microbiological criteria. Factors associated with in-hospital, 30-day, and 90-day mortality were evaluated. RESULTS: A total of 128 patients with rheumatic diseases who had a positive quantitative polymerase chain reaction assay for Pneumocystis jirovecii were screened, and 72 patients were included in the final analysis. The median (interquartile range [IQR]) pneumonia severity index (PSI) was 101.5 (77.0-132.0). The median (IQR) adjunctive corticosteroid dosage was 0.6 (0.4-0.9) mg/kg/day prednisolone equivalent. The receiver operating characteristic curve analysis showed that the optimal cutoff point of median adjunctive corticosteroid dosage was 0.6 mg/kg/day to predict in-hospital, 30-day, and 90-day mortality. In the multivariable logistic regression analysis, median adjunctive corticosteroid dosage ≥0.6 mg/kg/day and PSI >90 were independent factors of in-hospital, 30-day, and 90-day mortality. CONCLUSION: A median adjunctive corticosteroid dosage of ≥0.6 mg/kg/day might be associated with mortality in patients with rheumatic diseases complicated by PCP.

Molecular Basis for Paradoxical Activities of Polymorphonuclear Neutrophils in Inflammation/Anti-Inflammation, Bactericide/Autoimmunity, Pro-Cancer/Anticancer, and Antiviral Infection/SARS-CoV-II-Induced Immunothrombotic Dysregulation.

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cells in the circulation. These cells act as the fast and powerful defenders against environmental pathogenic microbes to protect the body. In addition, these innate inflammatory cells can produce a number of cytokines/chemokines/growth factors for actively participating in the immune network and immune homeostasis. Many novel biological functions including mitogen-induced cell-mediated cytotoxicity (MICC) and antibody-dependent cell-mediated cytotoxicity (ADCC), exocytosis of microvesicles (ectosomes and exosomes), trogocytosis (plasma membrane exchange) and release of neutrophil extracellular traps (NETs) have been successively discovered. Furthermore, recent investigations unveiled that PMNs act as a double-edged sword to exhibit paradoxical activities on pro-inflammation/anti-inflammation, antibacteria/autoimmunity, pro-cancer/anticancer, antiviral infection/COVID-19-induced immunothrombotic dysregulation. The NETs released from PMNs are believed to play a pivotal role in these paradoxical activities, especially in the cytokine storm and immunothrombotic dysregulation in the recent SARS-CoV-2 pandemic. In this review, we would like to discuss in detail the molecular basis for these strange activities of PMNs.

Distinguishing different types of attention deficit hyperactivity disorder in children using artificial neural network with clinical intelligent test.

Background: Attention deficit hyperactivity disorder (ADHD) is a well-studied topic in child and adolescent psychiatry. ADHD diagnosis relies on information from an assessment scale used by teachers and parents and psychological assessment by physicians; however, the assessment results can be inconsistent. Purpose: To construct models that automatically distinguish between children with predominantly inattentive-type ADHD (ADHD-I), with combined-type ADHD (ADHD-C), and without ADHD. Methods: Clinical records with age 6-17 years-old, for January 2011-September 2020 were collected from local general hospitals in northern Taiwan; the data were based on the SNAP-IV scale, the second and third editions of Conners' Continuous Performance Test (CPT), and various intelligence tests. This study used an artificial neural network to construct the models. In addition, k-fold cross-validation was applied to ensure the consistency of the machine learning results. Results: We collected 328 records using CPT-3 and 239 records using CPT-2. With regard to distinguishing between ADHD-I and ADHD-C, a combination of demographic information, SNAP-IV scale results, and CPT-2 results yielded overall accuracies of 88.75 and 85.56% in the training and testing sets, respectively. The replacement of CPT-2 with CPT-3 results in this model yielded an overall accuracy of 90.46% in the training set and 89.44% in the testing set. With regard to distinguishing between ADHD-I, ADHD-C, and the absence of ADHD, a combination of demographic information, SNAP-IV scale results, and CPT-2 results yielded overall accuracies of 86.74 and 77.43% in the training and testing sets, respectively. Conclusion: This proposed model distinguished between the ADHD-I and ADHD-C groups with 85-90% accuracy, and it distinguished between the ADHD-I, ADHD-C, and control groups with 77-86% accuracy. The machine learning model helps clinicians identify patients with ADHD in a timely manner.

Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis.

Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-α, and TNF-α, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11/U12 RNP), anti-nucleolar antigens (anti-Th/T0, anti-NOR90, anti-Ku, anti-RuvBL1/2, and anti-PM/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammation exists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.

Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia: State-of-the-art and future perspectives.

Metabolic disturbances and obesity are major cardiovascular risk factors in patients with schizophrenia, resulting in a higher mortality rate and shorter life expectancy compared with those in the general population. Although schizophrenia and metabolic disturbances may share certain genetic or pathobiological risks, antipsychotics, particularly those of second generation, may further increase the risk of weight gain and metabolic disturbances in patients with schizophrenia. This review included articles on weight gain and metabolic disturbances related to antipsychotics and their mechanisms, monitoring guidelines, and interventions. Nearly all antipsychotics are associated with weight gain, but the degree of the weight gain varies considerably. Although certain neurotransmitter receptor-binding affinities and hormones are correlated with weight gain and specific metabolic abnormalities, the precise mechanisms underlying antipsychotic-induced weight gain and metabolic disturbances remain unclear. Emerging evidence indicates the role of genetic polymorphisms associated with antipsychotic-induced weight gain and antipsychotic-induced metabolic disturbances. Although many guidelines for screening and monitoring antipsychotic-induced metabolic disturbances have been developed, they are not routinely implemented in clinical care. Numerous studies have also investigated strategies for managing antipsychotic-induced metabolic disturbances. Thus, patients and their caregivers must be educated and motivated to pursue a healthier life through smoking cessation and dietary and physical activity programs. If lifestyle intervention fails, switching to another antipsychotic drug with a lower metabolic risk or adding adjunctive medication to mitigate weight gain should be considered. Antipsychotic medications are essential for schizophrenia treatment, hence clinicians should monitor and manage the resulting weight gain and metabolic disturbances.

The FcγRIII Engagement Augments PMA-Stimulated Neutrophil Extracellular Traps (NETs) Formation by Granulocytes Partially via Cross-Talk between Syk-ERK-NF-κB and PKC-ROS Signaling Pathways.

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cell in the circulation capable of neutrophil extracellular traps (NETs) formation after stimulation. Both NADPH oxidase-dependent and -independent pathways are involved in NET formation. The IgG is the most abundant immunoglobulin in human serum. However, the impact of the circulating IgG on NET formation is totally unexplored. In this study, the all-trans retinoic acid (ATRA)-induced mature granulocytes (dHL-60) were pre-treated with monomeric human IgG, papain-digested Fab fragment, crystallizable IgG Fc portion, rituximab (a human IgG1), or IgG2. The NET formation of the dHL-60 in the presence/absence of phorbol 12-myristate 13-acetate (PMA) stimulation was then measured by the fluorescent area after SYTOX green nucleic acid stain. The intracellular reactive oxygen species (ROS) generation was measured by flow cytometry. Total and phosphorylated Syk, SHP-1, and ERK were detected by immunoblot. We found that human monomeric IgG and its subclasses IgG1 and IgG2 per se induced negligible NET formation of dHL-60, but the FcγRIII engagement by these IgG subclasses and Fc portion augment PMA-stimulated dHL-60 NET formation in a dose-dependent manner. Furthermore, we found that increased Syk and ERK phosphorylation, intracellular ROS generation, and pro-inflammatory cytokines, IL-8 and TNF-α, production could be induced after FcγRIII engagement. Blocking FcγRIII engagement by a specific antibody diminished the augmented NET formation. In conclusion, we discovered that cross-talk between FcγRIII engagement-induced Syk-ERK and PMA-induced PKC signaling pathways augment NET formation of dHL-60 via increased ROS generation and pro-inflammatory cytokines, IL-8 and TNF-α, production.

Pregnancy outcomes in patients treated with belimumab: Report from real-world experience.

OBJECTIVE: To investigate the neonatal and maternal outcomes of patients treated with belimumab during pregnancy. MATERIALS AND METHODS: We retrospectively collected patients who were treated with belimumab during pregnancy from January 2018 to October 2020 in a tertiary referral hospital in Taiwan. All patients had clinical and serological features of systemic lupus erythematosus or antiphospholipid syndrome and had been treated accordingly. The patients' medical and obstetric history, obstetric complications and fetal outcomes were collected by chart review. RESULTS: A total of 13 pregnancies in 13 patients were included. The median age was 38 years (interquartile range 32-41 years), 46.2% had a history of recurrent pregnancy loss, and the median number of treatment courses with belimumab (400 mg per dose) was two. There were 11 live births (84.6%, 11 of 13). One episode of omphalitis was noted in one fetus, who recovered well with antibiotic treatment. No fetus had leukopenia, lymphopenia, neutropenia, or thrombocytopenia in the days after birth. No fetal anomalies were found in this series. Among the six patients with a past history of recurrent pregnancy loss, four had live births. CONCLUSION: This study provides new evidence for the use of belimumab in pregnant patients. No increase in the risk of fetal anomalies or severe infection was noted in the patients who were exposed to belimumab during pregnancy. Cautious monitoring is necessary if belimumab is used in pregnant patients, and more data are still needed to validate its safety.

Progressive multifocal leukoencephalopathy in systemic lupus erythematosus managed with pembrolizumab: A case report with literature review.

Progressive multifocal leukoencephalopathy (PML) is one of the rare but lethal infectious complication in patients with SLE, manifesting progressive central nervous demyelination caused by JC virus (JCV). There have been no effective antiviral agents so far; however, immune checkpoint inhibitors (ICI) have been demonstrated as potential treatments by reinvigorating antiviral T-cell activity against JC virus. To date, sixteen PML cases treated with anti-PD-1 have been reported; however, there was no report addressing the use of ICI in patients with concomitant PML and rheumatic disease, possibly due to the concern for possible autoimmune disease flare-up. In addition, treatment outcomes of these ICI-treated cases were heterogeneous. Experiences from these cases suggested that high disease burden, JC viral load in CSF, and severe immunosuppression status at baseline may predict poor response to treatment. Our case, a 62-year-old woman with long-standing SLE, turned out to have a delayed but effective response to prolonged ICI treatment despite of her high JC viral load and immunosuppressed status caused by high-dose steroid and rituximab. To our knowledge, this is the first case report with SLE complicated with PML clinically improved by pembrolizumab treatment without consequent immune related adverse events (irAE). Considering the lethal nature of PML and absence of effective medication, ICI is a reasonable consideration in patients with SLE and progressive PML.

Clinicopathological and molecular features between synchronous and metachronous metastases in colorectal cancer.

The molecular difference between synchronous and metachronous metastases in colorectal cancer (CRC) remains unclear. Between 2000 and 2010, a total of 492 CRC patients were enrolled, including 280 with synchronous metastasis and 212 with metachronous metastasis. Clinicopathological and molecular features were compared between the two groups. Patients with synchronous metastasis were more likely to have right-sided CRC, poorly differentiated tumors, lymphovascular invasion, advanced pathological tumor (T) and node (N) categories, and liver metastases than those with metachronous metastasis. For right-sided CRC, patients with synchronous metastasis had more lymphovascular invasion and liver metastases than those with metachronous metastasis. For left-sided CRC, patients with synchronous metastasis were more likely to have poorly differentiated tumors, lymphovascular invasion, advanced pathological T and N categories, and liver metastases than those with metachronous metastasis. Regarding the genetic mutations, patients with metachronous metastasis had more mutations in TP53, NRAS, and HRAS and fewer mutations in APC than those with synchronous metastasis; for right-sided CRC, synchronous metastasis was associated with more APC mutations than metachronous metastasis, while for left-sided CRC, metachronous metastasis was associated with more TP53 and NRAS mutations than synchronous metastasis. The 5-year overall survival (OS) rates were significantly higher in metachronous metastasis patients than in synchronous metastasis patients, especially those with left-sided CRC. Multivariate analysis showed that age, sex, lymphovascular invasion, pathological N category, metachronous metastasis, and BRAF and NRAS mutations were independent prognostic factors affecting OS. CRC patients with synchronous metastasis had a worse OS than those with metachronous metastasis and exhibited distinct genetic mutations.