Anti-N-methyl-D-aspartate Receptor Encephalitis in People Living with HIV: Case Report and Literature Review.

With the increase in the number of cases of autoimmune encephalitis (AE), the cerebrospinal fluid (CSF) of people living with HIV (PLWH) showing abnormal behavior, cognitive impairment or abnormal movements should be actively screened for the antibody panel of AE. Early recognition and treatment can prevent severe seizures or coma and markedly improve the prognosis of patients. The first-line immunotherapy for AE includes intravenous methylprednisolone and immunoglobulin. However, whether long-time immunosuppressive maintenance therapy is needed is debated. For PLWH, immunosuppressive therapy and even steroids could be more challenging. Here, we review and summarize the clinical characteristics often reported cases and report one case from our center to improve the diagnosis and treatment of anti-N-methyl-D-aspartate receptor encephalitis in PLWH.

Distinct Lipidomic Profiles between People Living with HIV Treated with E/C/F/TAF or B/F/TAF: An Open-Label Prospective Cohort Study.

INTRODUCTION: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) has been increasingly replaced by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in the treatment of human immunodeficiency virus (HIV) owing to its more favorable pharmacokinetics and fewer drug-drug interactions. However, the effect of this switch on plasma lipids and lipidomic profiles remains poorly characterized. METHODS: HIV infected patients on an E/C/F/TAF regimen were recruited into the study and followed up every 12 weeks. Participants were divided into E/C/F/TAF and B/F/TAF groups depending on whether they were switched to B/F/TAF during follow-up. Clinical information and blood samples were collected at 0, 12, and 24 weeks, and lipidomic analysis was performed using liquid chromatography mass spectrometry. RESULTS: No significant differences were observed between the groups at baseline. At week 24, patients switched to B/F/TAF had lower triglyceride [mmol/L; 1.23 (0.62) versus 2.03 (0.75), P = 0.001] and very low-density lipoprotein cholesterol [mmol/L; 0.64 (0.26) versus 0.84 (0.32), P = 0.037) compared with patients who continued E/C/F/TAF therapy. Small decrease from baseline in Framingham general cardiovascular risk score (FRS) was observed in the B/F/TAF arm [week (W) 0: 2.59 (1.57) versus W24: 2.18 (1.01), P = 0.043]. Lipidomic analysis indicated that E/C/F/TAF treatment increased the levels of several diglycerides (DGs), triacylglycerols (TAGs), and lyso-phosphatidylcholines (LPCs), whereas switching to B/F/TAF led to increased sphingolipids and glycerophospholipids. After adjusting for demographic and clinical parameters, only DG (16:0/18:2), DG (18:2/22:6), DG (18:3/18:2), DG (20:5/18:2), TAG (18:3/18:2/21:5), TAG (20:5/18:2/22:6), and LPC (22:6) were found to be significantly associated with FRS (regression coefficient of 0.17-6.02, P < 0.05). Most of these FRS associate lipid species were significantly elevated in individuals treated with E/C/F/TAF instead of individuals treated with B/F/TAF. CONCLUSION: E/C/F/TAF promotes the accumulation of lipid species closely associated with cardiovascular disease (CVD) risk among people living with HIV, whereas B/F/TAF has a decreased impact on CVD-related lipid profile and is associated with lower CVD risk. A graphical abstract is available with this article. TRIAL REGISTRATION: ClinicalTrials.gov; identifier, NCT06019273.

Bidirectional motion characteristics of resonant inertial impact rotating piezoelectric motor based on self-clamping structure.

A new working principle for multimodal excitation of a resonant bidirectional rotary inertial impact piezoelectric motor with a self-clamping structure was developed based on previous research on piezoelectric motors. Unlike previous piezoelectric motors that relied on single harmonic waves for unidirectional rotation, in this motor, we can simply change the driving signal characteristics of the motor without changing the structure of the piezoelectric motor to excite multiple vibration modes, thereby achieving rotation in both directions. Compared with other bidirectional resonant motors, the structure and control signal are simpler. The finite element simulation software COMSOL5.5 was used to simulate the working mode of the motor, and the results were in good agreement with the final experiment. During the experiments, the optimal operating frequency of the motor prototype was 900 Hz. The maximum output speed of the motor prototype was 3.9 rad/s, the maximum output torque was 15 N mm, and the maximum resolution was 0.248° under the conditions of 240 Vp-p voltage, 900 Hz frequency, and 7.8 N mm preload torque.

A resonant inertial impact rotary piezoelectric motor based on a self-clamping structure.

A resonant inertial impact rotary piezoelectric motor based on a self-clamping structure is designed, assembled, and tested. The designed piezoelectric motor mainly includes a rotor (two vibrators, preload mechanism, and intermediate connection mechanism), a clamping mechanism, and another auxiliary mechanism. The piezoelectric ceramic sheet on the rotor drives the vibrator to swing under the excitation of a single harmonic wave. Because there is a clamping mechanism formed by the combination of clamp baffle and fixed clamp ring, thus the half-cycle resonant rotation of the rotor can be effectively completed, and repeated harmonic excitation can realize the unidirectional continuous rotation and swing of the rotor. The whole excitation process of the motor is in a resonance state, which has significant advantages, such as low friction and simple structure, compared with the traditional quasi-static piezoelectric motor. The structure of the piezoelectric motor is designed and analyzed using COMSOL5.5 software and then the motor performance is tested and analyzed by building an experimental platform to verify the feasibility of the motor design. The final experimental results show that the optimal working frequency of the piezoelectric motor is 150 Hz, which is consistent with the characteristic frequency of the simulation. When the motor prototype is under the conditions of optimal operating frequency 150 Hz, voltage 240 Vp-p, and preload torque 7.8 N.mm, the maximum angular speed can reach 2.4 rad/s, the maximum load can reach 27.8 N mm and the maximum resolution of the movement angle can reach 0.941°.

Research on the bidirectional motion of resonant single-wing bionic piezoelectric motor based on a biasing self-clamping mechanism.

Based on our previous research, this article adds new research content and further refines the previous research on bionic motors. It is in the form of note as a complementary improvement to the previous article. This article proposes a novel approach to achieving reversal motion in such motors driven by a single harmonic signal, specifically the multimode mode of the vibrator. In contrast to the conventional inertial impact piezoelectric motor, we propose a bidirectional piezoelectric motor that can achieve bidirectional motion only by altering the driving signal characteristics. Compared to other bidirectional piezoelectric motors, this motor features a simpler structure and more convenient control. The COMSOL6.0 finite element analysis software was utilized to optimize the working mode of the piezoelectric motor, and an experimental platform was constructed for testing and verifying the performance of the designed prototype. The final experimental data demonstrate that, with an excitation voltage of 300 Vp-p, a preload of 2 N, and an excitation frequency of 781 Hz, the motor prototype achieves a maximum no-load speed of 12.15 mm/s, a maximum resolution of 15.27 µm, and a maximum load of 14 g. These results confirm the validity of the new working mode.

A resonant single-wing bionic piezoelectric motor based on a biasing self-clamping mechanism.

In this study, a resonant single-wing bionic piezoelectric motor based on a biasing self-clamping mechanism inspired by dragonfly flight was designed, assembled, and tested. The main mechanism of the designed piezoelectric motor includes a mover (including a vibrator, clamping foot, bionic pedestal, etc.), a stator, and other auxiliary components. The clamping foot of the mover contacts the side of the stator to form a biasing self-clamping mechanism, which can achieve a clamping effect within half a cycle of the vibrator's resonant vibration. The piezoelectric plate on the vibrator receives a single harmonic excitation from the signal generator, causing the base plate to bend and distort. The base plate drives the clamping foot to move regularly, causing the mover to perform a linear motion. Moreover, repeated single harmonic excitations can realize the continuous movement of the mover. The structure of the piezoelectric motor was optimized using COMSOL6.0, which is a finite element analysis software. The first-order bending vibration of the vibrator was chosen as the working mode through finite element simulation, and an experimental platform was built. The performance of the prototype piezoelectric motor was tested and verified on the experimental platform. The final experimental data show that under the conditions of 300 Vp-p excitation voltage and 109 Hz driving frequency, the maximum no-load speed of the prototype reaches 6.184 mm/s, and the maximum load of the motor is 4 g.

Epstein-Barr virus variation in people living with human immunodeficiency virus in southeastern China.

BACKGROUND: Patients infected with HIV are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. The genotype and viral biological behavior of EBV infection in patients with human immunodeficiency virus-1 (HIV) in China remain unclear. This study analyzed the characteristics of EBV in patients infected with HIV in southeastern China. METHODS: A total of 162 HIV-infected patients and 52 patients without HIV were enrolled in this study. EBV viral load in blood was determined by fluorescence quantitative PCR. EBV typing was performed using saliva according to polymorphisms in the EBNA3C region. EBV LMP-1 carboxy terminus (C-ter) was sequenced, and compared with the epidemic strains in the world. RESULTS: Among HIV infected patients, the EBV strain variant was mainly EBV-1, while EBV-2 had a higher viral load than EBV-1 (P = 0.001) and EBV-1/2 (P = 0.002). HIV infected patients had higher active virus replication. The EBV LMP-1 variants were mainly the China1 variant. HIV-infected patients had different nucleic acid positions of 30-bp deletion (del30) and had a higher incidence of high 33-bp tandem repeats (rep33) copies than non-HIV-infected patients. There was a difference in the mutations of EBV LMP-1 C-ter del30 and ins15 between HIV infected patients and the control group (P < 0.001). CONCLUSION: In southeastern China, EBV in HIV-infected patients had higher active virus replication; EBV infection was mainly EBV-1, and EBV-2 infection has higher EBV virus load; hotspot mutations of LMP-1 C-ter were different between HIV-infected patients and non-HIV-infected patients. TRIAL REGISTRATION: This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2018764), and registered in Chinese Clinical Trial Registry on 3 June 2019 (ChiCTR, ChiCTR1900023600, http://www.chictr.org.cn/usercenter.aspx ).

Efficacy and safety of lenalidomide in HIV-associated cryptococcal meningitis patients with persistent intracranial inflammation: an open-label, single-arm, prospective interventional study.

BACKGROUND: Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined. METHODS: We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide. RESULTS: Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7-3.2) g/L at baseline to 0.9 (0.6-1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4-149.8) mg/L at baseline to 55.3 (38.3-89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed. CONCLUSION: Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.

Case report: Ruxolitinib as first-line therapy for secondary hemophagocytic lymphohistiocytosis in patients with AIDS.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a fatal immunological syndrome resulting from excessive production of inflammatory cytokines. The conventional therapies for HLH, which are based on cytotoxic agents, are not always efficacious and safe, especially in patients with severe immunodeficiency. Ruxolitinib, a strong inhibitor of Janus kinase (JAK) 1/2, has already been evaluated as salvage and first-line therapy for HLH. Despite its promising efficacy and tolerability in the treatment of secondary HLH, the efficacy and safety of ruxolitinib in HLH patients with HIV infection remain to be investigated. Case presentation: Two men (ages: 45 and 58 years) both presented at our hospital with a high fever. They were found to be HIV-positive with severe immunodeficiency and opportunistic infections. Their laboratory tests showed severe pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and increased levels of inflammatory factors and ferritin. Hemophagocytosis was found in the bone marrow, and abdominal computed tomography or ultrasonography showed splenomegaly. Both patients were diagnosed with infection-induced HLH due to severe immunodeficiency. Given they were both highly immunocompromised, we chose ruxolitinib as a first-line treatment alternative to cytotoxic chemotherapy. Rapid remission of clinical symptoms and normalization of laboratory parameters were achieved after ruxolitinib therapy. Neither patient had any associated adverse drug reactions or other laboratory abnormalities. Both patients were eventually discharged and ruxolitinib was discontinued as their disease alleviated, and they did not show signs of relapse during the 3- and 5-month of follow-up examinations. Conclusion: We described two cases of AIDS-related secondary HLH treated with ruxolitinib. Our cases highlight the feasibility of using ruxolitinib as a first-line therapy in patients with HIV infection and secondary HLH. Nevertheless, the safety and efficacy of this novel treatment need to be evaluated in large clinical trials in the future.

Lenalidomide potentially reduced the level of cell- associated HIV RNA and improved persistent inflammation in patients with HIV-associated cryptococcal meningitis a pilot study.

Background: The HIV-1 reservoir is a major barrier to curative strategies. Inflammation is an important factor for HIV-1 reservoir persistence. Lenalidomide regulates inflammatory cytokines efficiently. We examined whether lenalidomide could inhibit HIV-1 transcription and reduce systemic inflammation in people living with HIV. Methods: Lenalidomide was administered orally for 48 weeks to patients with HIV-associated cryptococcal meningitis (HIV-CM). A HIV-1 latency model was treated with or without lenalidomide ex vivo for 5 days. The primary endpoints were change in HIV reservoir markers and inflammatory cytokines in both the cohort and cell model. Results: Thirteen participants were enrolled from May 2019 to September 2020. The median change in cell-associated (CA) HIV RNA between baseline and 48 weeks was 0.81 log10 copies/million peripheral blood mononuclear cells (PBMCs). The CA HIV RNA decreased significantly in the cohort (P = 0.021). Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gradually diminished with lenalidomide treatment until 48 weeks (P = 0.007, P = 0.014, respectively). C-reactive protein/IL-6/TNF-α and CA HIV RNA were significantly correlated (P = 0.0027, 0.0496, and 0.0346, respectively). Lenalidomide also significantly decreased HIV core P24 (P = 0.0038) and CA HIV RNA in CD8-depleted PBMCs (P = 0.0178) ex vivo. TNF-α and IL-6 were significantly reduced in the CD8-depleted PBMC supernatant (P = 0.004, P < 0.0001, respectively) while IL-10 levels increased significantly on lenalidomide compared to no-lenalidomide treatment (P < 0.0001). Conclusions: Lenalidomide was preliminarily confirmed to reduce the level of cell- associated HIV RNA and improve persistent inflammation in patients with HIV-Associated cryptococcal meningitis, which was a potential intervention for clinical use to inhibit viral transcription of the HIV-1 reservoir and reduced HIV-related inflammation in HIV-1 patients during ART.

Pharmacological Treatment of Vascular Dementia: A Molecular Mechanism Perspective.

Vascular dementia (VaD) is a neurodegenerative disease, with cognitive dysfunction attributable to cerebrovascular factors. At present, it is the second most frequently occurring type of dementia in older adults (after Alzheimer's disease). The underlying etiology of VaD has not been completely elucidated, which limits its management. Currently, there are no approved standard treatments for VaD. The drugs used in VaD are only suitable for symptomatic treatment and cannot prevent or reduce the occurrence and progression of VaD. This review summarizes the current status of pharmacological treatment for VaD, from the perspective of the molecular mechanisms specified in various pathogenic hypotheses, including oxidative stress, the central cholinergic system, neuroinflammation, neuronal apoptosis, and synaptic plasticity. As VaD is a chronic cerebrovascular disease with multifactorial etiology, combined therapy, targeting multiple pathophysiological factors, may be the future trend in VaD.

HIV-1LAI Nef blocks the development of hematopoietic stem/progenitor cells into T lymphoid cells.

OBJECTIVE: Despite successful antiviral therapy, the recovery of CD4+ T cells may not be complete in certain HIV-1-infected individuals. In our previous work with humanized mice infected with CXCR4-tropic HIV-1LAI (LAI), viral protein Nef was found the major factor determining rapid loss of both CD4+ T cells and CD4+CD8+ thymocytes but its effect on early T-cell development is unknown. The objective of this study is to investigate the influence of LAI Nef on the development of hematopoietic stem/progenitor cells (HSPCs) into T lymphoid cells. DESIGN: HSPC-OP9-DL1 cell co-culture and humanized mouse model was used to investigate the objective of our study in vitro and in vivo. RNA-seq was exploited to study the change of gene expression signature after nef expression in HSPCs. RESULTS: Nef expression in HSPCs was found to block their development into T lymphoid cells both in vitro and in the mice reconstituted with nef-expressing HSPCs derived from human cord blood. More surprisingly, in humanized mice nef expression preferentially suppressed the production of CD4+ T cells. This developmental defect was not the result of CD34+ cell loss. RNA-seq analysis revealed that Nef affected the expression of 176 genes in HSPCs, including those involved in tumor necrosis factor, Toll-like receptor, and nucleotide-binding oligomerization domain-like receptor signaling pathways that are important for hematopoietic cell development. CONCLUSION: Our results demonstrate that Nef compromises the development of HSPCs into T lymphoid cells, especially CD4+ T cells. This observation suggests that therapeutics targeting Nef may correct HIV-1-associated hematopoietic abnormalities, especially defects in T-cell development.

Clinical outcomes and prognostic factors of robotic assisted rectal cancer resection alone versus robotic rectal cancer resection with natural orifice extraction: a matched analysis.

Robotic rectal cancer resection with natural orifice extraction is a recently developed minimally invasive surgery used in the treatment of patients with rectal cancer. However, its safety and feasibility remain undiscussed and controversial. This study reported the clinical outcomes and prognostic factors pertaining to traditional robotic assisted rectal cancer resection alone against that of robotic rectal cancer resection with natural orifice extraction to provide a discussion on this issue. 49 patients who underwent robotic rectal cancer resection with natural orifice extraction and 49 matched patients who underwent conventional robotic assisted rectal cancer resection were systematically analyzed in this study. Regarding the baseline characteristics, after matching, no significant differences were observed between the natural orifice specimen extraction (NOSE) group and the robotic assisted rectal cancer resection (RARC) group. Patients in the NOSE group had a reduced visual analog scale (p < 0.001), passed flatus more quickly (p = 0.002) and suffered less surgical stress than those in the RARC group. Moreover, 4 complications were observed in the NOSE group and 7 complications in the RARC group with no significant difference (p = 0.337) in terms of complications. The two groups had a similar survival outcomes, where the 3-year overall survival (p = 0.738) and 3-year progression-free survival (p = 0.986) were all comparable between the two groups. Histological differentiation and T stage could be regarded as independent prognostic factors for 3-year overall survival and 3-year progression-free survival. Robotic rectal cancer resection with natural orifice extraction is a safe and feasible minimally invasive surgery for patients suffering from rectal cancer as it encompasses considerable several advantages. Histological differentiation and T stage may serve as independent prognostic factors for 3-year overall survival and 3-year progression-free survival.

[Advances in the role of autoantibodies in diabetic nephropathy: Review].

Diabetic nephropathy (DN) is the most common cause of global end-stage renal disease (ESRD) and is one of the leading causes of mortality in patients with type 1 and type 2 diabetes. Recent studies have found that autoimmunity is closely related to the occurrence and development of DN, especially the autoantibodies which play a crucial role in the pathogenesis of DN. Currently, autoantibodies found in the serum of DN patients mainly include G-protein coupled receptor autoantibodies, pancreatic autoantibodies and autoantibodies related to endothelial cell damage. In the special environment of diabetes, high glucose (HG) can stimulate the production of a variety of autoantibodies, which can mediate the damage of renal function via different mechanisms and affect the progression of DN. Therefore, it is important to explore the role of autoantibodies in the pathogenesis of DN.

Regulatory T cells and T helper 17 cells in viral infection.

CD4+ T cells are the central element of the adaptive immune responses and protect the body from a variety of pathogens. Starting from naive cells, CD4+ T cells can differentiate into various effector cell subsets with specialized functions including T helper (Th) 1, Th2, Th17, regulatory T (Treg) and T follicular helper (Tfh) cells. Among them, Tregs and Th17 cells show a strong plasticity allowing the functional adaptation to various physiological and pathological environments during immune responses. Although they are derived from the same precursor cells and their differentiation pathways are interrelated, the terminally differentiated cells have totally opposite functions. Studies have shown that Tregs and Th17 cells have rather complex interplays in viral infection: Th17 cells may contribute to immune activation and disease progression while Tregs may inhibit this process and play a key role in the maintenance of immune homoeostasis, possibly at the cost of compromised viral control. In this review, we take respiratory syncytial virus (RSV), hepatitis B virus (HBV)/hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections as examples to discuss these interplays and their impacts on disease progression in viral infection.