Toward the Improvement of the Mechanical and Tribological Properties of Braided Ligament for ACL Reconstruction: A "Carrot and Stick" Strategy.

Bone tunnel enlargement has been troubling the clinical adoption of braided artificial ligaments for decades, to which mechanical and tribological performance promotion shall be an effective and promising approach. Herein, a "carrot and stick" strategy has been introduced with two types of polyethylene terephthalate (PET) fibers to fabricate hybrid textures, which is expected to advance fatigue and tribological performance without yielding essential mechanical strength and biocompatibility. Owing to advancements in such a "carrot and stick" strategy, the obtained grafts present three promising properties: i) enhancement of mechanical strength; ii) coefficient of friction (COF) reduction of 25% at the greatest extent, thus lowering the risk of bone tunnel enlargement; iii) final displacement shrinkage of graft length after cyclic loadings, favored in the clinic for isometric reconstruction. The results obtained in this study show that the "carrot and stick" strategy can be a creative and convenient method to optimize the service life, saving the complication rate of artificial ligaments for clinical applications.

Composite Interventions on Outcomes of Severely and Critically Ill Patients with COVID-19 in Shanghai, China.

Background: The sixty-day effects of initial composite interventions for the treatment of severely and critically ill patients with COVID-19 are not fully assessed. Methods: Using a Bayesian piecewise exponential model, we analyzed the 60-day mortality, health-related quality of life (HRQoL), and disability in 1082 severely and critically ill patients with COVID-19 between 8 December 2022 and 9 February 2023 in Shanghai, China. The final 60-day follow-up was completed on 10 April 2023. Results: Among 1082 patients (mean age, 78.0 years, 421 [38.9%] women), 139 patients (12.9%) died within 60 days. Azvudine had a 99.8% probability of improving 2-month survival (adjusted HR, 0.44 [95% credible interval, 0.24-0.79]), and Paxlovid had a 91.9% probability of improving 2-month survival (adjusted HR, 0.71 [95% credible interval, 0.44-1.14]) compared with the control. IL-6 receptor antagonist, baricitinib and a-thymosin each had a high probability of benefit (99.5%, 99.4%, and 97.5%, respectively) compared to their controls, while the probability of trail-defined statistical futility (HR > 0.83) was high for therapeutic anticoagulation (99.8%; HR, 1.64 [95% CrI, 1.06-2.50]) and glucocorticoid (91.4%; HR, 1.20 [95% CrI, 0.71-2.16]). Paxlovid, Azvudine, and therapeutic anticoagulation showed a significant reduction in disability (p < 0.05) Conclusions: Among severely and critically ill patients with COVID-19 who received 1 or more therapeutic interventions, treatment with Azvudine had a high probability of improved 60-day mortality compared with the control, indicating its potential in a resource-limited scenario. Treatment with an IL-6 receptor antagonist, baricitinib, and a-thymosin also had high probabilities of benefit in improving 2-month survival, among which a-thymosin could improve HRQoL. Treatment with Paxlovid, Azvudine, and therapeutic anticoagulation could significantly reduce disability at day 60.

Adaptive immunology of Cryptococcus neoformans infections-an update.

The fungal genus Cryptococcus comprises a group of pathogens with considerable phenotypic and genotypic diversity that can lead to cryptococcosis in both healthy and immunocompromised individuals. With the emergence of the HIV pandemic, cryptococcosis, mainly meningoencephalitis, afflicts HIV-infected patients with severe dysfunction of T cells. It has also been reported in recipients of solid organ transplantation and in patients with autoimmune diseases who take immunosuppressive agents long-term, as well as in those with unidentified immunodeficiency. The clinical outcome of the disease is primarily determined by the immune response resulting from the interplay between the host immune system and the pathogen. Most human infections are caused by Cryptococcus neoformans, and nearly all immunological studies have focused on C. neoformans. This review provides an updated understanding of the role of adaptive immunity during infection with C. neoformans in human and animal models over the past half-decade.

Clinical Progression and Outcome of Hospitalized Patients Infected with SARS-CoV-2 Omicron Variant in Shanghai, China.

BACKGROUND: Studies on the Omicron variant infection have generally been restricted to descriptions of its initial clinical and epidemiological characteristics. We investigated the timeline-related progression and clinical outcome in hospitalized individuals with the Omicron variant. METHODS: We conducted a retrospective, single-centered study including 226 laboratory-confirmed cases with the Omicron variant between 6 April and 11 May 2022 in Shanghai, China. The final date of follow-up was 30 May 2022. RESULTS: Among 226 enrolled patients, the median age was 52 years, and 118 (52.2%) were female. The duration from onset of symptoms to hospitalization was 3 days (interquartile range (IQR): 2-4 days) for symptomatic patients. Cough occurred in 168 patients (74.3%). The median interval to negative reverse-transcriptase PCR tests of nasopharynx swab was 10 days ((IQR): 8-13 days). No radiographic progressions were found in 196 patients on the 7th day after onset of symptoms. The median duration of fever in all participants was 5 days (IQR: 4-6 days). The median PCR conversion time of Paxlovid-treated patients was 8 days (IQR: 7-10 days) compared with that of a traditional Chinese herb medicine lianhuaqingwen (10 days, IQR: 8-13 days) (p = 0.00056). Booster vaccination can significantly decrease the severity of Omicron infection when compared with unvaccinated patients (p = 0.009). In multivariate logistic analysis, erythrocyte sedimentation rate (ESR) (OR = 1.05) was independently related to the severity of the infection. CONCLUSIONS: The majority of clinical symptoms of Omicron infection were not severe. Early and aggressive administration of Paxlovid can significantly reduce the PCR conversion time. Booster vaccination should also be highly recommended in the population over 14 years old.

Early treatment regimens achieve sustained virologic remission in infant macaques infected with SIV at birth.

Early antiretroviral therapy (ART) in HIV-infected infants generally fails to achieve a sustained state of ART-free virologic remission, even after years of treatment. Our studies show that viral reservoir seeding is different in neonatal macaques intravenously exposed to SIV at birth, in contrast to adults. Furthermore, one month of ART including an integrase inhibitor, initiated at day 3, but not day 4 or 5 post infection, efficiently and rapidly suppresses viremia to undetectable levels. Intervention initiated at day 3 post infection and continued for 9 months achieves a sustained virologic remission in 4 of 5 infants. Collectively, an early intervention strategy within a key timeframe and regimen may result in viral remission or successful post-exposure prophylaxis for neonatal SIV infection, which may be clinically relevant for optimizing treatment strategies for HIV-infected or exposed infants.

Increased Proviral DNA in Circulating Cells Correlates with Plasma Viral Rebound in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Antiretroviral Therapy Interruption.

The human immunodeficiency virus (HIV) reservoir is responsible for persistent viral infection, and a small number of mosaic latent cellular reservoirs promote viral rebound upon antiretroviral therapy interruption, which is the major obstacle to a cure. However, markers that determine effective therapy and viral rebound posttreatment interruption remain unclear. In this study, we comprehensively and longitudinally tracked dynamic decay of cell-associated viral RNA/DNA in systemic and lymphoid tissues in simian immunodeficiency virus (SIV)-infected rhesus macaques on prolonged combined antiretroviral therapy (cART) and evaluated predictors of viral rebound after treatment cessation. The results showed that suppressive ART substantially reduced plasma SIV RNA, cell-associated unspliced, and multiply spliced SIV RNA to undetectable levels, yet viral DNA remained detectable in systemic tissues and lymphoid compartments throughout cART. Intriguingly, a rapid increase of integrated proviral DNA in peripheral mononuclear cells was detected once treatment was withdrawn, accompanied by the emergence of detectable plasma viral load. Notably, the increase of peripheral proviral DNA after treatment interruption correlated with the emergence and degree of viral rebound. These findings suggest that measuring total viral DNA in SIV infection may be a relatively simple surrogate marker of reservoir size and may predict viral rebound after treatment interruption and inform treatment strategies.IMPORTANCE Viral reservoirs are involved in persistent HIV infection, and a small number of mosaic latent cellular reservoirs promote viral rebound upon analytical treatment interruption, which is the major obstacle to a cure. However, early indicators that can predict resurgence of viremia after treatment interruption may aid treatment decisions in people living with HIV. Utilizing the rhesus macaque model, we demonstrated that increased proviral DNA in peripheral cells after treatment interruption, rather than levels of proviral DNA, was a useful marker to predict the emergence and degree of viral rebound after treatment interruption, providing a rapid approach for monitoring HIV rebound and informing decisions.

Mucosal integrin α4ß7 blockade fails to reduce the seeding and size of viral reservoirs in SIV-infected rhesus macaques.

Cellular viral reservoirs are rapidly established in tissues upon HIV-1/SIV infection, which persist throughout viral infection, even under long-term antiretroviral therapy (ART). Specific integrins are involved in the homing of cells to gut-associated lymphoid tissues (GALT) and inflamed tissues, which may promote the seeding and dissemination of HIV-1/SIV to these tissue sites. In this study, we investigated the efficacy of prophylactic integrin blockade (α4ß7 antibody or α4ß7/α4ß1 dual antagonist TR-14035) on viral infection, as well as dissemination and seeding of viral reservoirs in systemic and lymphoid compartments post-SIV inoculation. The results showed that blockade of α4ß7/α4ß1 did not decrease viral infection, replication, or reduce viral reservoir size in tissues of rhesus macaques after SIV infection, as indicated by equivalent levels of plasma viremia and cell-associated SIV RNA/DNA to controls. Surprisingly, TR-14035 administration in acute SIV infection resulted in consistently higher viremia and more rapid disease progression. These findings suggest that integrin blockade alone fails to effectively control viral infection, replication, dissemination, and reservoir establishment in HIV-1/SIV infection. The use of integrin blockade for prevention or/and therapeutic strategies requires further investigation.

The use of bidirectional rapid reductor in minimally invasive treatment of bicondylar tibial plateau fractures: preliminary radiographic and clinical results.

BACKGROUND: Minimally invasive treatment of complex tibial plateau fracture represents one of the most challenging problems in orthopedic surgery. We intended to describe the percutaneous surgery involving an originally designed traction device which might facilitate the closed reduction for bicondylar tibial plateau fractures. Further, to assess the clinical outcomes of this minimally invasive technique. METHODS: Between December 2015 and July 2016, Twenty-one patients, mean age 43.71 ± 13.80 years, suffering from a bicondylar tibial plateau fracture (AO/OTA 41-type C) were included. All fractures were firstly reduced by skeletal traction with the aid of bidirectional rapid reductor, and residual depressed fragments were treated with minimally invasive bone tamp reduction. We then evaluated at a minimum follow-up of one year: (1) the rate of complications, (2) the radiographic outcomes (the amount of depression, tibial plateau widening, tibial plateau angle and posterior slope angle) and (3) the clinical outcome (Rasmussen scoring system). RESULTS: All patients had their fractures healed without secondary displacement. No instrument-related complications occurred during operation. Post-operatively, superficial infection was found in two patients and donor-site morbidity was found in one patient. We observed a < 5 mm step-off in 100% of patients and a < 5 mm plateau widening in 95.5% of patients. Three patients were considered indicative of malalignment with TPA > 90° or PSA > 15°. At last evaluation, the Rasmussen clinical score was excellent in 11 patients (52.3%), good in 9 (42.9%) and fair in 1 (4.8%), and the radiological score was excellent in seven patients (33.3%), good in 14 (66.7%). CONCLUSIONS: The bidirectional rapid reductor facilitates the minimally invasive treatment of bicondylar tibial plateau fracture. The patients exhibited excellent functional recovery. These results should be validated with a larger group of patients and longer period results. TRIAL REGISTRATION: ChiCTR-OPC-16008011 .

Impaired Development and Expansion of Germinal Center Follicular Th Cells in Simian Immunodeficiency Virus-Infected Neonatal Macaques.

Germinal center (GC) CD4+ follicular Th (Tfh) cells are critical for cognate B cell help in humoral immune responses to pathogenic infections. Although Tfh cells are expanded or depleted in HIV/SIV-infected adults, the effects of pediatric HIV/SIV infection on Tfh cells remain unclear. In this study, we examined changes in lymphoid follicle formation in lymph nodes focusing on GC Tfh cells, B cell development, and differentiation in SIV-infected neonatal rhesus macaques (Macaca mulatta) compared with age-matched cohorts. Our data showed that follicles and GCs of normal infants rapidly formed in the first few weeks of age, in parallel with increasing GC Tfh cells in various lymphoid tissues. In contrast, GC development and GC Tfh cells were markedly impaired in SIV-infected infants. There was a very low frequency of GC Tfh cells throughout SIV infection in neonates and subsequent infants, accompanied by high viremia, reduction of B cell proliferation/resting memory B cells, and displayed proinflammatory unresponsiveness. These findings indicate neonatal HIV/SIV infection compromises the development of GC Tfh cells, likely contributing to ineffective Ab responses, high viremia, and eventually rapid disease progression to AIDS.

Anti-retroviral therapy decreases but does not normalize indoleamine 2,3-dioxygenase activity in HIV-infected patients.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO), which is mainly expressed in activated dendritic cells, catabolizes tryptophan to kynurenine and other downstream catabolites. It is known to be an immune mediator in HIV pathogenesis. The impact of anti-retroviral therapy on its activity has not been well established. METHODS: We measured systemic IDO activity (the ratio of plasma kynurenine to tryptophan) in HIV-infected patients before and after highly active antiretroviral therapy (HAART) and its association with a microbial translocation marker, soluble CD14 (sCD14). RESULTS: Among 76 participants, higher baseline IDO activity was associated with lower CD4+ T cell counts (P<0.05) and higher plasma sCD14 levels (P<0.001). After 1 year of HAART, IDO activity decreased significantly (P<0.01), but was still higher than in healthy controls (P<0.05). The baseline IDO activity did not predict CD4+ T cell recovery after 1 year of therapy. The percentages of myeloid and plasmacytoid dendritic cells were not correlated with IDO activity. CONCLUSIONS: IDO activity is elevated in HIV-infected patients, which is partially associated with microbial translocation. HAART reduced, but did not normalize the activity of IDO.

Genetic relatedness of human immunodeficiency virus-1 (HIV-1) strains in a 12-year-old daughter and her father in a household setting.

Modalities of intra-familial transmission of HIV-1 are not always clear. Here we describe an uncommon case of HIV transmission in a family setting, analyzed using clinical, epidemiological and nucleic-acid-based methods, and assess risk factors for intrafamilial transmission of HIV-1 infection. All sequences from the father and the daughter were grouped in the same cluster with a 100 % bootstrap value, which means that the father and his daughter were infected with highly homologous CRF01_AE. The diversity of genetic clones between env and pol genes was insignificant (p > 0.05). Moreover, the results of analysis of drug-resistance-associated mutation positions of the two viral isolates were almost identical, indicating that both were susceptible to the first-line anti-HIV drugs prior to the initiation of antiretroviral treatment (ART), and this presented additional evidence of a high similarity between the two family members' HIV-1 quasispecies. In this family, HIV-1 isolates from a father and his daughter had very highly genetic relatedness. By combining their clinical histories, we could draw the conclusion that the daughter was probably infected via contact with her father's blood or other body fluids, but no obvious transmission route was found, suggesting that HIV-1 infection in similar household settings should be taken into consideration whenever the origin of HIV-1 infection cannot be identified.

Identification of human immunodeficiency virus-1 (HIV-1) transmission from a 29-year-old daughter to her mother in Shanghai, China.

BACKGROUND AND METHODS: Routes of intrafamilial transmission of HIV-1 are not always clear. Here, we describe transmission to a mother from her 29-year-old daughter within a family setting through clinical, epidemiological and molecular evidence. We evaluated the risk factors for intrafamilial transmission of HIV-1 infection through qualitative epidemiology following pol and env gene sequencing and phylogenetic analysis. RESULT: The nucleotide sequences of the pol and env genes of the two strains from the two patients in the family were 99 % and 100 % identical, respectively, and they clustered with CRF07_BC, which includes the main recombinant strains in Shanghai, China. The diversity of genetic clones between the env and pol genes was insignificant (p > 0.05). The drug-resistance-associated mutation positions of the two viral strains were basically similar and indicated that both were susceptible to the first-line anti-retroviral drugs including zidovudine (AZT), lamivudine (3TC), efavirenz (EFV) and nevirapine (NVP) prior to the initiation of highly active antiretroviral treatment (HAART), providing additional evidence of a close similarity between the quasispecies of the two family members. CONCLUSION: In this family, the two strains of the virus, isolated from the mother and her adult daughter, had very high homology. In the context of their clinical histories, we can make a conclusion that the mother was infected by the virus in her daughter's blood or other body fluids, but no overt transmission route has been clarified. This investigation also suggested that intimate personal exposure in the same household can contribute to HIV-1 transmission and underscores the need to educate persons who care for or are in contact with HIV-infected persons in household settings where such exposures may occur.