Coronavirus Disease 2019-Associated Neurological Manifestations in Children: A Large Single-Center Experience With Rare Cases.

BACKGROUND: We aimed to analyze pediatric patients with coronavirus disease 2019 (COVID-19) with a diverse spectrum of neurological manifestations in a single center since neurological involvement in children is still poorly understood. METHODS: We performed a retrospective study on 912 children aged between zero and 18 years who had a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result and symptoms of COVID-19 from March 2020 to March 2021 in a single center. RESULTS: Among 912 patients, 37.5% (n = 342) had neurological symptoms and 62.5% (n = 570) had no neurological symptoms. The mean age of patients with neurological symptoms was significantly higher (14.2 ± 3.7 vs 9.9 ± 5.7; P < 0.001). Three hundred and twenty-two patients had nonspecific symptoms (ageusia, anosmia, parosmia, headache, vertigo, myalgia), whereas 20 patients had specific involvement (seizures/febrile infection-related epilepsy syndrome, cranial nerve palsy, Guillain-Barré syndrome and variants, acute disseminated encephalomyelitis, central nervous system vasculitis). The mean age of the patients with nonspecific neurological symptoms was significantly higher (14.6 ± 3.1 vs 7.7 ± 5.7; P < 0.001). CONCLUSION: This study presents a large number of patients with a diverse spectrum of neurological manifestations. The rare neurological manifestations reported in our study will contribute to better understanding the neurological involvement of SARS-CoV-2 in children. The study also points out the differences of SARS-CoV-2-related neurological manifestations between patients at different ages. Physicians should be alert about recognizing the early neurological manifestations of the SARS-CoV-2 in children.

Mortality in psoriatic arthritis patients, changes over time, and the impact of COVID-19: results from a multicenter Psoriatic Arthritis Registry (PsART-ID).

BACKGROUND: This study aimed to assess the mortality of PsA before and during the COVID-19 pandemic. METHODS: From the prospective, multicenter PsART-ID (Psoriatic Arthritis Registry-International Database), patients from Turkey were analyzed by linking the registry to the Turkish Cause of Death Registry. The outcome of interest was death from any cause, pre-pandemic (since the onset of registry-March 2014-March 2020), and during the pandemic (March 2020-May 2021). The crude mortality rate and standardized mortality ratio (SMR) were determined. RESULTS: There were 1216 PsA patients with a follow-up of 7500 patient-years. Overall, 46 deaths (26 males) were observed. In the pre-pandemic period, SMR for PsA vs the general population was 0.95 (0.61-1.49), being higher in males [1.56 (0.92-2.63)] than females [0.62 (0.33-1.17)]. The crude mortality rate in PsA doubled during the pandemic (pre-pandemic crude mortality rate: 5.07 vs 10.76 during the pandemic) with a higher increase in females (2.9 vs 8.72) than males (9.07 vs 14.73). CONCLUSION: The mortality in PsA was found similar to the general population in the pre-pandemic era. The mortality rates in PsA doubled during the pandemic. Whether PsA patients have more risk of mortality than the general population due to COVID-19 needs further studies. Key Points • Decrease in mortality in PsA might be expected with the more effective treatment options and better disease control. • A crude mortality rate is comparable to the general population and not increased until the pandemic. • Currently, there is a 2-fold increase in crude mortality rate possibly due to the COVID-19.

SARS-CoV-2 Delta Variant Decreases Nanobody Binding and ACE2 Blocking Effectivity.

The Delta variant spreads more rapidly than previous variants of SARS-CoV-2. This variant comprises several mutations on the receptor-binding domain (RBDDelta) of its spike glycoprotein, which binds to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors in host cells. The RBD-PD interaction has been targeted by antibodies and nanobodies to prevent viral infection, but their effectiveness against the Delta variant remains unclear. Here, we investigated RBDDelta-PD interactions in the presence and absence of nanobodies H11-H4, H11-D4, and Ty1 by performing 21.8 µs of all-atom molecular dynamics simulations. Unbiased simulations revealed that Delta variant mutations strengthen RBD binding to ACE2 by increasing the hydrophobic interactions and salt bridge formation, but weaken interactions with H11-H4, H11-D4, and Ty1. Among these nanobodies H11-H4 and H11-D4 bind RBD without overlapping ACE2. They were unable to dislocate ACE2 from RBDDelta when bound side by side with ACE2 on RBD. Steered molecular dynamics simulations at comparable loading rates to high-speed atomic force microscopy (AFM) experiments estimated lower rupture forces of the nanobodies from RBDDelta compared to ACE2. Our results suggest that existing nanobodies are less effective to inhibit RBDDelta-PD interactions and a new generation of nanobodies is needed to neutralize the Delta variant.

Effects of hydroxychloroquine and its metabolites in patients with connective tissue diseases.

Hydroxychloroquine has attracted attention in the treatment of COVID-19. Many conflicting findings have been reported regarding the efficacy and safety of this drug, which has been used safely in the rheumatological diseases for years. However, these studies lacked measurement methods that allow accurate assessment of hydroxychloroquine and its metabolite levels. The aim of this study was to measure hydroxychloroquine and its metabolite levels in whole blood samples of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and scleroderma (Scl) by a robust, simple and accurate validated tandem mass spectrometric method, and to investigate the relationship between these levels with drug-related adverse effects and disease activity scores. The validated LC-MS/MS method was applied to measure blood hydroxychloroquine and its metabolite levels of patients with RA, SLE, SS, Scl. Various haematological and biochemical parameters were measured with Beckman-Coulter AU 5800 and Beckman Coulter LH 780 analyzers, respectively. QTc intervals were calculated with Bazett's formula, and the patients were followed up by clinicians in terms of clinical findings and adverse effects. Hydroxychloroquine levels of patients were similar to previous studies. There was a negative correlation between disease activity scores and hydroxychloroquine levels, while the highest correlation was between QTc interval, creatinine and GFR levels with desethylchloroquine. Bidetylchloroquine had the highest correlation with RBC count and liver function tests. Our findings showed that hydroxychloroquine and its metabolite levels were associated with disease activity scores, renal, hepatic function, QTc prolongation, and hematological parameters.

Pain and Affected Symptoms of Patients with Rheumatoid Arthritis During COVID-19 Period.

BACKGROUND: Aim: The aim of this study is to determine the symptoms, pain, and function changes experienced by rheumatoid arthritis patients during the COVID-19 pandemic. METHOD: This descriptive study was completed with a total of 119 patients from the rheumatology clinic of a university hospital who met the follow-up research criteria and agreed to participate in the study. Descriptive features question form, pandemic period disease characteristics form, and Visual Analogue Scale were used to collect data. RESULTS: The mean age of the patients was 48.53 ± 10.24, the duration of the disease was 69.63 ± 37.02 months, the average visual analog scale values before the pandemic period were 3.77 ± 1.40, while the average visual analog scale values during the pandemic period were 5.02 ± 1.57. The most common patient complaints were hygiene problems (p < .001), dressing problems (p < .001), and nutritional problems (p < .001) due to increased pain during the pandemic period. It was determined that the patients needed a health care professional for self-care (p < .001), injections (p < .001), and pain management (p < .001) during the pandemic period. CONCLUSIONS: During the pandemic period, patients with rheumatoid arthritis (RA) stated that they needed the support of a health care professional for self-care, injections, and pain management.

Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells by binding its spike (S) glycoproteins to angiotensin-converting enzyme 2 (ACE2) receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonds between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and is the last to unbind from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove to be an effective strategy to inhibit S-ACE2 interactions.

Conformational transition of SARS-CoV-2 spike glycoprotein between its closed and open states.

In 2020, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide and caused the coronavirus disease 2019 (COVID-19). Spike (S) glycoproteins on the viral membrane bind to ACE2 receptors on the host cell membrane and initiate fusion, and S protein is currently among the primary drug target to inhibit viral entry. The S protein can be in a receptor inaccessible (closed) or accessible (open) state based on down and up positions of its receptor-binding domain (RBD), respectively. However, conformational dynamics and the transition pathway between closed to open states remain unexplored. Here, we performed all-atom molecular dynamics (MD) simulations starting from closed and open states of the S protein trimer in the presence of explicit water and ions. MD simulations showed that RBD forms a higher number of interdomain interactions and exhibits lower mobility in its down position than its up position. MD simulations starting from intermediate conformations between the open and closed states indicated that RBD switches to the up position through a semi-open intermediate that potentially reduces the free energy barrier between the closed and open states. Free energy landscapes were constructed, and a minimum energy pathway connecting the closed and open states was proposed. Because RBD-ACE2 binding is compatible with the semi-open state, but not with the closed state of the S protein, we propose that the formation of the intermediate state is a prerequisite for the host cell recognition.