Favipiravir induces HuNoV viral mutagenesis and infectivity loss with clinical improvement in immunocompromised patients.

Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution.

Unsupervised cluster analysis of clinical and ultrasound features reveals unique gout subtypes: Results from the Egyptian College of Rheumatology (ECR).

BACKGROUND: Gout comprises a heterogeneous group of disorders; however, comorbidities have been the focus of most efforts to classify disease subgroups. OBJECTIVES: We applied cluster analysis using musculoskeletal ultrasound (MSUS) combined with clinical and laboratory findings in patients with gout to identify disease phenotypes, and differences across clusters were investigated. PATIENTS AND METHODS: Patients with gout who complied with the ACR/EULAR classification criteria were enrolled in the Egyptian College of Rheumatology (ECR)-MSUS Study Group, a multicenter study. Selected variables included demographic, clinical, and laboratory findings. MSUS scans assessed the bilateral knee and first metatarsophalangeal joints. We performed a K-mean cluster analysis and compared the features of each cluster. RESULTS: 425 patients, 267 (62.8 %) males, mean age 54.2 ± 10.3 years were included. Three distinct clusters were identified. Cluster 1 (n = 138, 32.5 %) has the lowest burden of the disease and a lower frequency of MSUS characteristics than the other clusters. Cluster 2 (n = 140, 32.9 %) was mostly women, with a low rate of urate-lowering treatment (ULT). Cluster 3 (n = 147, 34.6 %) has the highest disease burden and the greatest proportion of comorbidities. Significant MSUS variations were found between clusters 2 and 3: joint effusion (p < 0.0001; highest: cluster 3), power Doppler signal (p < 0.0001; highest: clusters 2), and aggregates of crystal deposition (p < 0.0001; highest: cluster 3). CONCLUSION: Cluster analysis using MSUS findings identified three gout subgroups. People with more MSUS features were more likely to receive ULT. Treatment should be tailored according to the cluster and MSUS features.

A Systematic Review on the Clinical Pharmacokinetics of Cephalexin in Healthy and Diseased Populations.

Cephalexin is a first-generation ß-lactam antibiotic used in adults and pediatrics to treat various streptococcal and staphylococcal infections. This review aims to summarize and evaluate all the pharmacokinetic (PK) data on cephalexin by screening out all pertinent studies in human beings following the per oral (PO) route. By employing different online search engines such as Google Scholar, PubMed, Cochrane Central, and Science Direct, 23 studies were retrieved, among which nine were in healthy subjects, five in diseased ones, and the remaining were drug-drug, drug-food, and bioequivalence-related. These studies were included only based on the presence of plasma concentration-time profiles or PK parameters, i.e., maximum plasma concentration (Cmax), half-life (t1/2) area under the curve from time 0-infinity (AUC0-∞), and clearance (CL/F). A dose-proportional increase in AUC0-∞ and Cmax can be portrayed in different studies conducted in the healthy population. In comparison to cefaclor, Cmax was recorded to be 0.5 folds higher for cephalexin in the case of renal impairment. An increase in AUC0-∞ was seen in cephalexin on administration with probenecid, i.e., 117 µg.h/mL vs. 68.1 µg.h/mL. Moreover, drug-drug interactions with omeprazole, ranitidine, zinc sulfate, and drug-food interactions for cephalexin and other cephalosporins have also been depicted in different studies with significant changes in all PK parameters. This current review has reported all accessible studies containing PK variables in healthy and diseased populations (renal, dental, and osteoarticular infections, continuous ambulatory peritoneal dialysis) that may be favorable for health practitioners in optimizing doses among the latter.

Psoriasis paradox-infliximab-induced psoriasis in a patient with Crohn's disease: a case report and mini-review.

Biologic drugs are therapeutic modalities designed to inhibit specific cytokine signaling pathways. The introduction of these drugs in the management of autoimmune diseases has dramatically changed the treatment paradigm of chronic systemic immune-mediated inflammatory disorders. However, despite their overall acceptable safety profiles, paradoxical reactions have been reported in some real-life cases including case studies and clinical trials. In this study, we report a patient with Crohn's disease who developed infliximab-induced psoriasis vulgaris after starting infliximab treatment. In this case, infliximab was discontinued, and low-dose steroids and subcutaneous methotrexate were introduced to control both his psoriasis and bowel condition with satisfying responses.

Retraction: Complete Lumbar Spine Dislocation With Full Neurological Recovery.

[This retracts the article DOI: 10.7759/cureus.19249.].

The effectiveness of the anti-tumor necrosis factor therapy infliximab in neuro-Behçet's disease: a systematic review and meta-analysis.

OBJECTIVE: To study the effectiveness of infliximab for the treatment of refractory central neuro-Behçet's disease. METHODS: In this systematic review and meta-analysis, the research question was designed using the 'Population, Intervention, Comparator, and Outcomes' (PICO) model and the search methodology was developed according to the PRISMA statement. The study was registered on PROSPERO. Web of Science, PubMed, and Cochrane Library databases were searched for articles published in English between January 2000 and January 2020. Data were analysed using Meta-Essentials software, version 10.12. Treatment effect size was determined by a random effects model. Interstudy heterogeneity was explored using I2 statistics. Cumulative meta-analysis was conducted to assess the temporal trend for accumulating evidence. RESULTS: Twenty-one studies, comprising 64 patients (mean age, 38 .21 years and mean disease duration, 84.76 months) were included. Effect-size analysis showed that 93.7% of the treated patients in the analysis were responders to infliximab therapy (95% confidence interval 0.88, 0.993). There was no significant inter-study heterogeneity (I2 = 0%). Cumulative analysis showed accumulating evidence favoring increasing effectiveness over the last 20 years. CONCLUSION: Infliximab showed considerable therapeutic effectiveness in the treatment of refractory neuro-Behçet's disease.

Quality of Life Evaluation in Saudi Arabian Pediatric Patients with Primary Immunodeficiency Diseases Receiving 20% Subcutaneous IgG Infusions at Home.

BACKGROUND AND AIMS: Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG. METHODS: In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG. RESULTS: Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0-14 years). The patients' diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5-125 months). The QoL score showed a significant improvement in the patients' global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients' general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively). CONCLUSIONS: This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20% SCIG.

Human inherited complete STAT2 deficiency underlies inflammatory viral diseases.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

Copper sulfide and zinc oxide hybrid nanocomposite for wastewater decontamination of pharmaceuticals and pesticides.

In this work, hybrid nanocomposites of CuS QDs @ ZnO photocatalysts are fabricated through a facile microwave-assisted (MW) hydrothermal method as a green preparation process. The prepared photocatalysts (PCs) are employed under simulated sunlight (SL) for the degradation of ciprofloxacin, ceftriaxone, ibuprofen pharmaceuticals, methylene blue dye, and 2,4,5-trichlorophenoxyacetic acid (2,4-D) pesticide. The prepared photocatalysts are characterized in detail using several compositional, optical, and morphological techniques. The influence of the CuS (QDs) wt. % on morphological, structural, as well as photocatalytic degradation efficiency have been investigated. The small displacement between the (107) plane of CuS and the (102) plane of ZnO can confirmed the existence of lattice interaction, implying the formation of p-n heterojunctions. TEM and XRD results demonstrated that the CuS QDs are established and uniformly decorated on the surface of ZnO NRs, confirming the forming of an efficient CuS QDs @ ZnO heterojunction nanostructures. The CuS QDs @ ZnO hybrid nanocomposites showed enhancement in crystallinity, light absorption, surface area, separation of e-h pair and inhibition in their recombination at an interfacial heterojunction. In addition it is found that, 3 wt% CuS QDs @ ZnO has the foremost influence. The results showed improvement of photocatalytic activity of the 3% CuS QDs @ ZnO hybrid nanocomposite as compared to the bare ZnO nanorods. The impressive photocatalytic performance of CuS @ ZnO heterostructure nanorods may be attributed to efficient charge transfer. The prepared CuS QDs @ ZnO hybrid nanocomposites exhibited 100% removal for MB dye, after 45 min, and after 60 min for ibuprofen, ciprofloxacin pharmaceuticals, and 2.4.5 trichloro phenoxy acetic acid pesticide with the catalyst amount of 0.2 g/L. Although 100% removal of ceftriaxone pharmaceutical acheived after 90 min. In addition CuS QDs @ ZnO hybrid nanocomposites exhibited complete removal of COD for ibuprofen, ceftriaxone pharmaceuticals and 2.4.5 trichloro phenoxy acetic acid pesticide after 2 h with no selectivity. Briefly, 3% CuS QDs@ZnO hybrid nanocomposites can be considered as promising photoactive materials under simulated sunlight for wastewater decontamination.

The Emerging Era of Interventional Imaging in Rheumatology: An Overview During the Coronavirus Disease-2019 (COVID-19) Pandemic.

Imaging has long been taking its place in the diagnosis, monitor, and prognosis of rheumatic diseases. It plays a vital role in the appraisal of treatment. Key progress in the clinical practice of rheumatology is the innovation of advanced imaging modalities; such as musculoskeletal ultrasound (MSUS), computerized tomography (CT) and magnetic resonance imaging (MRI). These modalities introduced a promising noninvasive method for visualizing bone and soft tissues to enable an improved diagnosis. The use of MSUS in rheumatology is considered a landmark in the evolution of the specialty and its ease of use and many applications in rheumatic diseases make it a forerunner instrument in the practice. The use of MSUS among rheumatologists must parallel the development rate of the excellence revealed in the specialty. Moreover, innovative interventional imaging in rheumatology (III-R) is gaining fame and key roles in the near future for a comprehensive management of rheumatic diseases with precision. This review article throws light on the emergence of these robust innovations that may reshape the guidelines and practice in rheumatology, in particular, efforts to enhance best practice during the coronavirus disease 2019 (COVID-19) pandemic are endorsed.

Mortality and disease related comorbidities in systemic lupus erythematosus: Data from an Egyptian cohort.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with significant disease-related comorbidity and considerably high mortality. AIM OF THE WORK: Explore the survival rates and the spectrum of disease related comorbidities in an Egyptian cohort afflicted by SLE. METHODS: This is a single center observational cohort study performed in one of the leading medical Schools governmental hospitals for teaching and training in the North African region and Middle East sectors Kasr Alainy School of Medicine-Cairo University. Inclusion criteria: the investigators of the research question went for planned review of the medical records of adult SLE patients ≥16 years classified according to American College of Rheumatology (ACR) 1997 SLE classification criteria set forth by Hochberg, 1997 who received longitudinal clinical care during the time period from 1999 to 2019. Exclusion criteria: patients seen only once, other collagen vascular diseases, endocrinal, cardiovascular, or other multisystem disease diagnosed prior to the onset of SLE. DATA ANALYSIS: Survival was determined from the time of SLE diagnosis to the last contact or date of death. The cumulative probability of survival was estimated using Kaplan-Meier method. Differences in survival between patient groups were determined using the long-rank test. RESULTS: The study included records of two hundred and two SLE patients, 184 (91.1%) were females and 18 (8.9%) patients were males. The mean age at the time of diagnosis was 26.71 ± 7.93 years with a mean follow-up between mean: 6.6 ± 4.58 years, 34.15% had damage in at least one of the organ systems by Systemic Lupus International Collaborating Clinics American college of rheumatology damage index SLICC/ACR-DI in the first 6 months. Considering an outcome label of dead or alive at the end of follow-up period, results showed a total of 52 mortalities, 88.5% were females and 11.5% were males, mean age at death onset was 30.9 ± 8.8 years. Results of the Kaplan-Meier survival curve showed an overall cumulative probability of survival at 5, 10, 15, and 20 years after SLE diagnosis was 82.9, 68.8, 51.4, and 20.4%, respectively. CONCLUSION: The cumulative probability of survival at 5, 10, 15, and 20 years after SLE diagnosis was 82.9, 68.8, 51.4, and 20.4%, respectively.

Clinical and Immunological Features of Human BCL10 Deficiency.

The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we provide an in-depth description of an additional patient with autosomal recessive complete BCL10 deficiency caused by a nonsense mutation that leads to a loss of expression (K63X). Using mass cytometry coupled with unsupervised clustering and machine learning computational methods, we obtained a thorough characterization of the consequences of BCL10 deficiency in different populations of leukocytes. We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells. The patient had recurrent respiratory infections since early childhood, and showed a family history of lethal severe infectious diseases. Fortunately, hematopoietic stem-cell transplantation (HSCT) cured her. Overall, this report highlights the importance of early genetic diagnosis for the management of BCL10 deficient patients and HSCT as the recommended treatment to cure this disease.

Complete Lumbar Spine Dislocation With Full Neurological Recovery.

The thoracolumbar region is the most vulnerable segment of the spine to traumatic injuries. It represents a region of transition of the relatively fixed and immobile thoracic spine and flexible lumbar spine. Injuries to the thoracolumbar region often result from high-energy trauma. We present the case of a 24-year-old woman who was brought to the emergency department after a fall from a great height. She presented with severe back pain that was associated with the inability to move both of her lower limbs with absent sensation and loss of urinary and bowel continence. Otherwise, she was hemodynamically stable. The patient underwent a computed tomography scan of the abdomen and pelvis. It demonstrated a complete fracture-dislocation of the second lumbar vertebra relative to the first lumbar vertebra causing shortening of the vertebral column. The second lumbar vertebra had a complete lateral dislocation and appeared in the same axial plane as the first lumbar vertebra giving the appearance of a "double vertebrae" sign. The patient was prepared for emergency open reduction internal fixation with a posterior surgical approach. The operation was done under general anesthesia with the use of sensory-evoked potential responses to avoid any neurological injury. Good realignment of the thoracolumbar spine was achieved. Six months after the operation, the patient was asymptomatic and resumed her regular activities. Complete traumatic lateral dislocation of the lumbar spine is very rare. Early diagnosis of such fracture by computed tomography scan is crucial to avoid maneuvers that may cause unintended spinal cord injuries.

Systemic lupus erythematosus children in Egypt: Homeland spectrum amid the global situation.

OBJECTIVES: This study aims to present the manifestations of juvenile systemic lupus erythematosus (JSLE) across Egypt, to focus on age at onset and gender-driven influence on disease characteristics, and to compare findings to other countries. METHODS: The study included 404 Egyptian children with systemic lupus erythematosus (SLE) presenting to one of the specialized rheumatology centers corresponding to 13 major governorates. Juvenile cases age was ≤ 16°years at the time of recruitment. The SLE Disease Activity Index (SLEDAI) and damage index (DI) were assessed. RESULTS: The mean age was 13.2 ± 2.4°years; 355 females and 49 males (7.2:1), and the disease duration was 2.3 ± 1.6 years, while age at disease onset was 11.1 ± 2.5°years. Their SLEDAI was 13.5 ± 12.3, and DI, 0.36 ± 0.78. The overall estimated prevalence of childhood-SLE patients in the recruited cohort in Egypt was 1/100,000 population (0.24/100000 males and 1.8/100000 females). 7.4% developed pre-pubertal SLE (≤ 7 years); 73.3%, peri-pubertal; and 19.3% during early adolescence. The differences according to age group were equal for gender and clinical manifestations except skin lesions present in 59.3% of pre-pubertal onset, 74.6% of peri-pubertal, and 84.2% of adolescents (p = 0.029), and renal involvement in 73.8% of peripubertal, 62.1% of pre-pubertal and 58.9% of adolescents (p = 0.03). Laboratory investigations, SLEDAI, and DI were similar among age categories. Lupus nephritis was more common in Egypt compared to JSLE from other countries. CONCLUSION: Our large multicenter study identified that female gender influenced disease characteristics with more frequent skin involvement. Skin lesions were significantly higher in adolescents, while renal involvement in peri-pubertal children.

Rheumatology university faculty opinion on coronavirus disease-19 (COVID-19) vaccines: the vaXurvey study from Egypt.

OBJECTIVES: The aim of the present work was to explore the perspectives of Egyptian Rheumatology staff members as regards the coronavirus disease-19 (COVID-19) vaccine. METHODS: The survey is composed of 25 questions. Some questions were adapted from the global rheumatology alliance COVID-19 survey for patients. RESULTS: 187 rheumatology staff members across Egypt from 18 universities and authorizations actively participated with a valid response. The mean time needed to complete the survey was 17.7 ± 13 min. Participants were 159 (85%) females (F:M 5.7:1). One-third agreed that they will be vaccinated once available, 24.6% have already received at least one dose, 29.4% are unsure while 16% will not take it. Furthermore, 70.1% agreed that they will recommend it to the rheumatic diseases (RD) patients once available, 24.1% are not sure while 5.9% will not recommend it. RD priority to be vaccinated against COVID-19 in descending order include SLE (82.9%), RA (55.1%), vasculitis (51.3%), systemic sclerosis (39.6%), MCTD (31.6%), Behcet's disease (28.3%). The most common drugs to be avoided before vaccination included biologics (71.7%), DMARDs (44.4%), biosimilars (26.7%), IVIg (17.1%) and NSAIDs (9.1%). CONCLUSIONS: The results of the study and specifically the low rate of acceptability are alarming to Egyptian health authorities and should stir further interventions to reduce the levels of vaccine hesitancy. As rheumatic disease patients in Egypt were not systematically provided with the vaccine till present, making the vaccine available could as well enhance vaccine acceptance. Further studies to investigate any possible side effects, on a large scale of RD patients are warranted.

Autoantibodies to extractable nuclear antigens (ENAs) pattern in rheumatoid arthritis patients: Relevance and clinical implications.

OBJECTIVES: To study the frequency of different autoantibodies to extractable nuclear antigens (ENAs) in rheumatoid arthritis (RA) patients and to correlate findings with clinical manifestations, disease activity and radiological damage. METHODS: A total of 230 RA patients were included and 75 healthy controls. In all patients rheumatological assessment was done and routine laboratory investigations and immune profile were performed in both patients and controls, including: RF, ACPA, ANA and anti-ENAs (Ro/SSA, La/SSB, U1-RNP, anti-Jo-1 and anti-Sm). Radiological damage was scored using Sharp/van der Heijde, and disease activity was evaluated by DAS28-ESR and DAS28-CRP. RESULTS: RF was positive in 101 (43.9%), ACPA in 220 (95.7%), ANA in 58 (25.2%), anti Ro in 31 (13.5%), anti-La in 10 (4.3%), anti-Jo1 in 5 (2.2%) and anti-RNP in 2 (0.9%). Anti-Ro/SSA positively correlated with sicca symptoms (p=.02), RF titer (p<.001), ANA (p<.001), DAS28-ESR (p=.026), and DAS28-CRP (p=.003). Anti-La antibodies correlated positively with SJC (p=.001), TJC (p=.001), ANA (p<.001), DAS-28 ESR (p=.007). Anti-Jo-1 correlated positively with interstitial lung disease (ILD) (p≤.001), RF titer (p=.037) and ANA (p≤.001). Anti-RNP antibodies correlated positively with disease duration (p≤.001), ACPA titer (p≤.001) and ANA (p=.014). In the controls ANA was positive in two (2.7%), anti-Ro in three (4%), and none of the controls tested positive for other autoantibodies. CONCLUSIONS: In RA patients, positive ANA is frequent and positively associated with anti-Ro, anti-La and anti-Jo1 autoantibodies. Screening for autoantibodies against other anti-ENAs seems mandatory in RA patients especially when ANA is positive. RA cases with positive Anti-Jo-1 may develop anti synthetase syndrome and ILD.