The effects of antihypertensive drugs on glucose metabolism.

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long-term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while ß-receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use.

Improving the diagnosis of active tuberculosis: a novel approach using magnetic particle-based chemiluminescence LAM assay.

OBJECTIVES: Tuberculosis (TB) is a significant global health concern, given its high rates of morbidity and mortality. The diagnosis using urine lipoarabinomannan (LAM) primarily benefits HIV co-infected TB patients with low CD4 counts. The focus of this study was to develop an ultra-sensitive LAM assay intended for diagnosing tuberculosis across a wider spectrum of TB patients. DESIGN & METHODS: To heighten the sensitivity of the LAM assay, we employed high-affinity rabbit monoclonal antibodies and selected a highly sensitive chemiluminescence LAM assay (CLIA-LAM) for development. The clinical diagnostic criteria for active TB (ATB) were used as a control. A two-step sample collection process was implemented, with the cutoff determined initially through a ROC curve. Subsequently, additional clinical samples were utilized for the validation of the assay. RESULTS: In the assay validation phase, a total of 87 confirmed active TB patients, 19 latent TB infection (LTBI) patients, and 104 healthy control samples were included. Applying a cutoff of 1.043 (pg/mL), the CLIA-LAM assay demonstrated a sensitivity of 55.2% [95%CI (44.13%~65.85%)], and a specificity of 100% [95%CI (96.52%~100.00%)], validated against clinical diagnostic results using the Mann-Whitney U test. Among 11 hematogenous disseminated TB patients, the positive rate was 81.8%. Importantly, the CLIA-LAM assay consistently yielded negative results in the 19 LTBI patients. CONCLUSION: Overall, the combination of high-affinity antibodies and the CLIA method significantly improved the sensitivity and specificity of the LAM assay. It can be used for the diagnosis of active TB, particularly hematogenous disseminated TB.

High Cytomegalovirus Viral Load Is Associated With 182-Day All-Cause Mortality in Hospitalized People With Human Immunodeficiency Virus.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with increased mortality in persons with HIV (PWH). It is less clear whether CMV infection is still associated with mortality when routinely screened and adequately treated. METHODS: This retrospective cohort study recruited 1003 hospitalized adults with HIV with CD4 cell counts <200 cells/µL from May 2017 to June 2021. Blood CMV DNA was routinely measured and CMV DNAemia was treated if end-organ disease occurred. CMV viral load was categorized into below the limit of quantification (BLQ; <500 IU/mL), low viral load (LVL; 500-10 000 IU/mL), and high viral load (HVL; ≥10 000 IU/mL) groups. We compared the 182-day all-cause mortality among different groups. RESULTS: The median (IQR) CD4 cell count of patients was 33 (13-84) cells/µL. The prevalence of CMV DNAemia was 39.8% (95% CI: 36.7-42.9%) and was significantly associated with CD4 cell count. The 182-day all-cause mortality was 9.9% (95% CI: 8.0-11.7%). Univariable analysis showed that, compared with BLQ, LVL and HVL were associated with 1.73-fold and 3.81-fold increased risks of mortality, respectively (P = .032 and P < .001). After adjustment for predefined confounding factors, HVL but not LVL was still associated with increased risk of mortality (adjusted hazard ratio: 2.63; 95% CI: 1.61-4.29; P < .001). However, for patients on effective antiretroviral therapy, the impact of HVL on 182-day mortality was not significant (P = .713). CONCLUSIONS: High CMV viral load in hospitalized PWH was associated with higher mortality, even when identified early by screening. Optimalization of the management for those patients needs to be explored in future studies.

miR-129-5p Plays an Anticancer Role in Colon Cancer by Targeting RSF1.

This study aimed to investigate the inhibitory effect of miR-129-5p on colon cancer by targeting RSF1. For this purpose, real-time quantitative PCR was used to analyze whether the expression of miR-129-5p in colon cancer and adjacent normal tissues had an impact on the proliferation and apoptosis of cancer cells (CC). We evaluated the role of miR-129-5p by targeting RSF1 in colon cancer tissue in the experimental group. But in the control group, only miR-129-5p was considered as a protective factor. Finally, we retrospectively analyzed data of 56 cases of colon cancer patients admitted to our clinical department between January 2019 and December 2019. Twenty-eight cases were investigated through just miR-129-5p protective factors for cancer (group A). The other 28 cases were studied by miR-129-5p anti-cancer agent and a completed RSF1 carcinoma factors for cancer (group B). We evaluated the comparative analysis of the patient's age and gender, clinical indicators (including for the first time of hospitalization and postoperative hospital stay, three times of anal exhaust), and complications (including chills, vomiting, hypertension, diabetes). The results showed that miR-129-5p had a more substantial effect on the proliferation and apoptosis of CC by targeting RSF1.

A comparative study of forest methods for time-to-event data: variable selection and predictive performance.

BACKGROUND: As a hot method in machine learning field, the forests approach is an attractive alternative approach to Cox model. Random survival forests (RSF) methodology is the most popular survival forests method, whereas its drawbacks exist such as a selection bias towards covariates with many possible split points. Conditional inference forests (CIF) methodology is known to reduce the selection bias via a two-step split procedure implementing hypothesis tests as it separates the variable selection and splitting, but its computation costs too much time. Random forests with maximally selected rank statistics (MSR-RF) methodology proposed recently seems to be a great improvement on RSF and CIF. METHODS: In this paper we used simulation study and real data application to compare prediction performances and variable selection performances among three survival forests methods, including RSF, CIF and MSR-RF. To evaluate the performance of variable selection, we combined all simulations to calculate the frequency of ranking top of the variable importance measures of the correct variables, where higher frequency means better selection ability. We used Integrated Brier Score (IBS) and c-index to measure the prediction accuracy of all three methods. The smaller IBS value, the greater the prediction. RESULTS: Simulations show that three forests methods differ slightly in prediction performance. MSR-RF and RSF might perform better than CIF when there are only continuous or binary variables in the datasets. For variable selection performance, When there are multiple categorical variables in the datasets, the selection frequency of RSF seems to be lowest in most cases. MSR-RF and CIF have higher selection rates, and CIF perform well especially with the interaction term. The fact that correlation degree of the variables has little effect on the selection frequency indicates that three forest methods can handle data with correlation. When there are only continuous variables in the datasets, MSR-RF perform better. When there are only binary variables in the datasets, RSF and MSR-RF have more advantages than CIF. When the variable dimension increases, MSR-RF and RSF seem to be more robustthan CIF CONCLUSIONS: All three methods show advantages in prediction performances and variable selection performances under different situations. The recent proposed methodology MSR-RF possess practical value and is well worth popularizing. It is important to identify the appropriate method in real use according to the research aim and the nature of covariates.

A special symptom of olfactory dysfunction in coronavirus disease 2019: report of three cases.

Three patients of coronavirus disease (COVID-19) showed the symptoms of olfactory dysfunction. Clinical characteristics and treatment were retrospective analyzed. Olfactory disorders are uncommon symptoms of COVID-19 in China. Early diagnosis and intervention are keys to the recovery of olfactory disorders. Particular attention should be devoted to olfactory dysfunction.

Characterization of dendritic cell (DC)-10 in recurrent miscarriage and recurrent implantation failure.

During pregnancy, the maternal immune system must tolerate the persistence of semi-allogeneic fetus in the maternal tissue. Inadequate recognition of fetal antigens may lead to pregnancy complications, such as recurrent miscarriage (RM) and recurrent implantation failure (RIF). Dendritic cells (DCs) are key regulators of protective immune responses and the development and maintenance of tolerance. Regarding that DCs are important in the establishment of immune tolerance in human pregnancy, it would be important to study the microenvironment in which DCs reside or are activated may affect their functions toward tolerance rather than active immune response. IL-10 plays a critical role in the maintenance of normal pregnancy, and the increased production of IL-10 is associated with successful pregnancy. In this study, we provide an in-depth comparison of the phenotype and cytokine production by DC-10 and other DC subsets, such as iDC and mDC. CD14+ monocyte-derived DCs were differentiated in the presence of IL-10 (DC-10) in vitro from ten normal fertile controls, six RM women and seven RIF women, and characterized for relevant markers. DC-10 was characterized by relatively low expression of costimulatory molecule CD86, as well as MHC class II molecule HLA-DR, high expression of tolerance molecules HLA-G, ILT2, ILT4 and immunosuppressive cytokine IL-10, but produced little or no proinflammatory cytokines, such as TNF-α, IL-6 and IL-12p70. Our study provides a better understanding of the phenotypical properties of DC-10, which may participate in the complex orchestration that leads to maternal immune tolerance and homeostatic environment in human pregnancy.

Metagenomic next-generation sequencing as a diagnostic tool for toxoplasmic encephalitis.

BACKGROUND: More than 100 different pathogens can cause encephalitis. Testing of all the neurological pathogens by conventional methods can be difficult. Metagenomic next-generation sequencing (NGS) could identify the infectious agents in a target-independent manner. The role of this novel method in clinical diagnostic microbiology still needs to be evaluated. In present study, we used metagenomic NGS to search for an infectious etiology in a human immunodeficiency virus (HIV)-infected patient with lethally diffuse brain lesions. Sequences mapping to Toxoplasma gondii were unexpectedly detected. CASE PRESENTATION: A 31-year-old HIV-infected patient presented to hospital in a critical ill condition with a Glasgow coma scale score of 3. Brain magnetic resonance imaging showed diffuse brain abnormalities with contrast enhancement. Metagenomic NGS was performed on DNA extract from 300 µL patient's cerebrospinal fluid (CSF) with the BGISEQ-50 platform. The sequencing detection identified 65,357 sequence reads uniquely aligned to the Toxoplasma gondii genome. Presence of Toxoplasma gondii genome in CSF was further verified by Toxoplasma gondii-specific polymerase chain reaction and Sanger sequencing. Altogether, those results confirmed the diagnosis of toxoplasmic encephalitis. CONCLUSIONS: This study suggests that metagenomic NGS may be a useful diagnostic tool for toxoplasmic encephalitis. As metagenomic NGS is able to identify all pathogens in a single run, it may be a promising strategy to explore the clinical causative pathogens in central nervous system infections with atypical features.

A health communication intervention to integrate partner testing with antiretroviral therapy service among men who have sex with men in China: an observational cohort study.

BACKGROUND: In China, antiretroviral therapy (ART) clinics focus on treating people living with HIV and are not required to undertake testing of high-risk populations. To improve partner testing among MSM, we implemented a health communication pilot intervention integrating partner testing with ART services. We aimed to assess the feasibility of the partner referral service and identify the predictors of both successful partner referral for HIV testing and HIV-positive test results among referred partners. METHODS: This program ran from April 2014 through December 2015 at designated ART clinics in six cities. The index participants, men living with HIV enrolled at an ART clinic, were assigned a case manager who assumed responsibility for routine ART-related counseling and mobilization of HIV-positive index participants for partner referral testing. Case managers were either nurses or contract staff. The successful referral rate was the proportion of index participants who referred a sexual partner for HIV testing. The HIV-positive partner rate was the proportion of the newly referred contacts who tested HIV-positive. Factors associated with the successful referral rate and the HIV-positive partner rate were assessed. RESULTS: Two thousand three hundred eighty-two index participants were enrolled. The median age was 30 years (IQR 26-37). 829index participants (34.80%) successfully referred at least one sexual partner for screening, and 92 (11.10%) referred partners were HIV-positive. Having a hospital nurse as case manager was associated with both successful partner referral (AHR = 1.56, 95% CI = 1.36-1.80) and having a HIV-positive partner (AHR = 2.35, 95% CI = 1.45-3.92). Index participants who were married (AHR = 1.44, 95% CI = 1.20-1.73) or employed (AHR = 1.29, 95% CI = 1.11-1.49) were more likely to successfully refer a partner for testing. Stable male partner relations were more likely to result in a referred partner testing HIV-positive (AHR = 5.50, 95% CI = 1.85-16.39). CONCLUSION: Our findings indicated that integration of MSM partner testing with ART services via health communication was feasible. Nurses as case managers effectively encouraged index participants to refer their sexual partners for HIV testing.

Causes of death in hospitalized children younger than 12 years of age in a Chinese hospital: a 10 year study.

BACKGROUND: In China, the majority (77%) of urban children die in hospitals. Hospital-based review could provide insight leading to improvements in clinical practice and increase the survival of critically ill children. The aim of the present study is to identify the trends of immediate causes and chronic underlying diseases associated with deaths of children at one of the largest teaching hospitals in China over a period of 10 years (2006-2015). METHODS: A retrospective analysis of data of all children aged 1 month to 11 years who died at Xinhua Hospital between 2006 and 2015. Demographic details, main causes of deaths, and chronic underlying diseases were reviewed. RESULTS: Case fatality rate was 0.55% (510/93,443) and it represented 0.41-0.80% deaths per year. Overall, the most common immediate causes of deaths in hospitalized children were pneumonia (36.7%), sepsis (13.5%), tumour (11.4%), followed by nontraumatic intracranial or gastrointestinal hemorrhage (10.6%) and cardiac shock (9.6%). Over 70% of the deaths in children were complicated with chronic underlying diseases. Congenital abnormality was the most frequent chronic underlying disease observed in infants (60.3%) and tumour was the main chronic underlying disease in toddlers (31.1%) and older children (44%). CONCLUSIONS: Infectious diseases, especially pneumonia, were the major immediate causes of deaths, and the mortality in the study population decreased with age. Tumour and other noninfectious disease accounted for more deaths in older children. Chronic underlying diseases were found in most deaths of children.

[Magnetic resonance imaging features of Cryptococcus infection in central nervous system in patients with AIDS].

OBJECTIVE: To investigate the magnetic resonance imaging (MRI) features of Cryptococcus infection in central nervous system patients with acquired immune deficiency syndrome (AIDS).
 Methods: The retrospective study on magnetic resonance imaging (MRI) and clinical data of cryptococcal meningitis (CM) was carried out between July 2011 and March 2017. These patients had not received anti-retroviral treatment. Patients with other specific or suspicious diseases in the central nervous system were not included in the analysis.
 Results: A total of 39 patients were included in the analysis, with CD4 cell counts of 13.0×106/L [(0-205)×106/L], and 94.9% (37/39) of patients with CD4 cell count <100×106/L. Of the 39 patients, 26 patients showed abnormal MRI signals in the brain, which were most frequently involved in the basal ganglia (20/26, 76.9%). The basal ganglia lesions showed dilated Virchow-Robin space (VRS)/gelatinous spseudocysts (18/20, 90%). Postcontrast T1-weighted MRI revealed no significant enhancement (3/5, 60%) and mild enhancement (2/5, 40%). The incidence of cerebral cryptococcal granuloma were 35% (7/20). Nineteen of 26 patients with lesions outside the basal ganglia, of which 13 patients also complicated with basal ganglia lesions. Postcontrast T1-weighted MRI revealed no significant enhancement. The incidence of cryptococcal granuloma and meningeal thickening were 15.7% (3/19) and 26.3% (5/19), respectively. Postcontrast T1-weighted MRI meningeal thickening revealed enhancement (5/5, 100%).
 Conclusion: The incidence of brain MRI abnormality in AIDS complicated with central nervous system Cryptococcus infection may not be low, and the lesions are mostly located in the basal ganglia. It most frequently displays the dilated VRS/gelatinous spseudocysts. It can also be showed cryptococcal granuloma. Postcontrast T1-weighted MRI often reveals no enhancement or mild enhancement.

Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis.

CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.

A Survey of the First-Hour Basic Care Tasks of Severe Sepsis and Septic Shock in Pediatric Patients and an Evaluation of Medical Simulation on Improving the Compliance of the Tasks.

BACKGROUND: Application of the sepsis resuscitation bundle is limited by clinician knowledge, skills, and experience. We used the adjusted first-hour basic care tasks in pediatric patients in three tertiary hospitals in Shanghai, China. OBJECTIVE: The aim of this study is to survey the compliance of the adjusted tasks and to evaluate in situ simulation team training on improving the compliance. METHODS: A prospective observational study was performed with the survey checklists from May 2011 to January 2012 in three pediatric intensive care units. A simulated case scenario was administered to the practitioners in one hospital. RESULTS: Seventy-three patients were enrolled, including 47 patients in one simulation hospital (SH) and 26 patients in two nonsimulation hospitals (NSH). The total compliance of the tasks was 47.9% (35/73). The compliance in the SH was significantly higher compared to that in the NSHs (61.7% [29/47] vs. 23.1% [6/26], p < 0.01). Compared to the SH, the main problems in the NSH were giving intravenous or intraosseous fluid resuscitation in a longer time (35.3 min vs. 19.9 min, p = 0.000), a smaller percentage of measurement of accurate urine output (38.5% vs. 68.1%, p = 0.027), delivering high-flow oxygen (73.1% vs. 93.6%, p = 0.028), and measurement of lactate (69.2% vs. 100%, p = 0.000). CONCLUSIONS: In situ simulation team training is an effective method of teaching the tasks of septic shock care to clinicians and nurses on the front line and of improving the compliance of the tasks.

CT semi-quantitative score used as risk factor for hyponatremia in patients with COVID-19: a cross-sectional study.

Purpose: Chest computed tomography (CT) is used to determine the severity of COVID-19 pneumonia, and pneumonia is associated with hyponatremia. This study aims to explore the predictive value of the semi-quantitative CT visual score for hyponatremia in patients with COVID-19 to provide a reference for clinical practice. Methods: In this cross-sectional study, 343 patients with RT-PCR confirmed COVID-19, all patients underwent CT, and the severity of lung lesions was scored by radiologists using the semi-quantitative CT visual score. The risk factors of hyponatremia in COVID-19 patients were analyzed and combined with laboratory tests. The thyroid function changes caused by SARS-CoV-2 infection and their interaction with hyponatremia were also analyzed. Results: In patients with SARS-CoV-2 infection, the total severity score (TSS) of hyponatremia was higher [M(range), 3.5(2.5-5.5) vs 3.0(2.0-4.5) scores, P=0.001], implying that patients with hyponatremia had more severe lung lesions. The risk factors of hyponatremia in the multivariate regression model included age, vomiting, neutrophils, platelet, and total severity score. SARS-CoV-2 infection impacted thyroid function, and patients with hyponatremia showed a lower free triiodothyronine (3.1 ± 0.9 vs 3.7 ± 0.9, P=0.001) and thyroid stimulating hormone level [1.4(0.8-2.4) vs 2.2(1.2-3.4), P=0.038]. Conclusion: Semi-quantitative CT score can be used as a risk factor for hyponatremia in patients with COVID-19. There is a weak positive correlation between serum sodium and free triiodothyronine in patients with SARS-CoV-2 infection.

Switch to fixed-dose ainuovirine, lamivudine, and tenofovir DF versus elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV-1: the 48-week results of the SPRINT trial, a multi-centre, randomised, double-blind, active-controlled, phase 3, non-inferiority trial.

Background: We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. Methods: This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Findings: Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. Interpretation: In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Funding: Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration.

Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.

Solitary cavitary pulmonary nodule may be a common CT finding in AIDS-associated pulmonary cryptococcosis.

BACKGROUND: Previous studies have demonstrated that the most common chest radiologic finding in acquired immune deficiency syndrome (AIDS)-associated pulmonary cryptococcosis (PC) is diffuse interstitial infiltrates. The aim of this study was to provide additional radiologic characterization of PC in AIDS patients. METHODS: AIDS patients from the Second Affiliated Hospital of the Southeast University who were diagnosed with cryptococcosis between February 2009 and May 2012 and who had undergone chest computed tomography (CT) scans before or at the time of diagnosis were retrospectively analyzed. RESULTS: Twelve patients met eligibility criteria. The median CD4 T-cell count was 23 cells/µl (range 2-79 cells/µl). Eleven patients had pulmonary abnormalities on imaging. Initial chest CT scans demonstrated solitary cavitary pulmonary nodules in 9 patients, pleural effusions in 2 patients, bilateral ground-glass opacities in 6 patients, patchy opacities in 1 patient, and bronchiectasis in 1 patient. Bilateral ground-glass opacities appeared to be associated with Pneumocystis pneumonia, while the presence of a pleural effusion was predictive of PC. Of the 9 solitary cavitary pulmonary nodules, 7 were PC and the other 2 were probable cases of PC. These nodules were predominantly in the peripheral lung and were either asymptomatic or caused only mild pulmonary symptoms. CONCLUSIONS: Solitary cavitary pulmonary nodule may be a common CT finding in AIDS-associated PC. All AIDS patients with solitary cavitary pulmonary nodules on chest CT should be screened for Cryptococcus infection.

Recurrent cryptococcal immune reconstitution inflammatory syndrome in an HIV-infected patient after anti-retroviral therapy: a case report.

Cryptococcal immune reconstitution inflammatory syndrome (C-IRIS) in HIV-infected patients presents as a clinical worsening or new presentation of cryptococcal disease as a result of anti-retroviral therapy mediated immune restoration. Recurrent C-IRIS is a rare condition. Recently, recurrent C-IRIS involving the central nervous system, which is thought to require prolonged or alternative immunosuppressive therapy, has been described. Here, we present an unusual case of recurrent C-IRIS, sequentially involving the central nervous system and lymph nodes, in an HIV-infected patient after anti-retroviral therapy. While corticosteroids were used to control the inflammatory cerebral cryptococcomas, lymphadenitis that developed after cessation of corticosteroids resolved without additional immunosuppressive or anti-inflammatory drugs. This case suggests the possibility of site-specific recovery of pathogen-specific immune response after anti-retroviral therapy. In this condition, each episode of C-IRIS may be treated independently, and extended corticosteroids may not always be needed.

Breakthrough of chemiluminescence-based LAM urine test beyond HIV-positive individuals: Clinical diagnostic value of pulmonary tuberculosis in the general population.

To investigate the diagnostic value of a novel high-sensitivity urine lipoarabinomannan (LAM) test (chemiluminescence-based) for active tuberculosis in the general population. A retrospective study was conducted on 250 clinical suspected tuberculosis patients who were HIV-negative and visited the Fourth People's Hospital of Foshan from January 2022 to December 2022. Among them, there were 135 cases of pulmonary tuberculosis, 34 cases of extrapulmonary tuberculosis, and 81 cases of non-tuberculosis. Urine samples were collected for LAM antigen detection before treatment, and laboratory data of sputum smear acid-fast staining (smear method), sputum culture, and GeneXpert method were collected. Using clinical diagnosis as the reference standard, the diagnostic efficacy of 4 methods for detecting active tuberculosis was evaluated. For the 135 cases of pulmonary tuberculosis, the sensitivity of sputum smears, sputm culture, sputm GeneXpert method, and urine LAM were 29.6% (40/135), 45.9% (62/135), 59.3% (80/135), and 51.9% (70/135), respectively. The combination of LAM + GeneXpert and LAM + culture had the highest sensitivity for detecting active pulmonary tuberculosis, which were 71.0% and 78.2%, respectively. For the detection of sputum culture-negative pulmonary tuberculosis, the positive rates of smear, GeneXpert, and LAM were 0.0% (0/73), 53.4% (39/73), and 52.1% (38/73), respectively. LAM + smear and LAM + Genexpert could detect 52.1% and 68.5% of sputum culture-negative patients, respectively. The high-sensitivity urine LAM test holds promise for tuberculosis diagnosis in the general population. It demonstrates high-sensitivity, enabling the detection of sputum culture-negative pulmonary tuberculosis patients. Furthermore, when combined with existing methods, it can enhance the overall detection rate.

Manual Acupuncture at LI11, Local Points and Both for Knee Osteoarthritis: A Pilot Randomized Controlled Trial.

Objective: Knee osteoarthritis (KOA) is a common chronic degenerative joint disease, and acupuncture is an alternative therapy for KOA. This study aims to detect the effectiveness of acupuncture at LI11 in improving pain and function for KOA patients. Methods: A total of 108 patients with KOA were randomly allocated to Control Group (local points), Treatment Group A (LI11), and Treatment Group B (local points and LI11) with a treatment phase of 4 weeks and a follow-up phase of 4 weeks. Primary outcome was response rate. Secondary outcomes included Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and recurrence rate. Study was registered on Chinese Clinical Trial Registry (Registered number: ChiCTR2000034926). Results: The response rate in Treatment Group A, Treatment Group B, and Control Group was 71.43%, 85.29%, and 51.53%, respectively, at Week 4, and Treatment Group B was significantly higher than Control Group (difference[98.3% CI]: 33.86[0.135,0.543], P = 0.003). Although no significant difference was found, Treatment Group A had a better response rate compared with Control Group (difference[98.3% CI]: 20.00 [-0.072, 0.472], P = 0.086). For VAS and WOMAC, there were significant differences within 3 groups at Week 4 compared with the baseline. There was a significant improvement in VAS scores and WOMAC function and pain subscales at Week 4 in Treatment Group B compared with Control Group and Treatment Group A. Conclusion: LI11 is an effective point for patients with KOA, and it could be a selection for young acupuncturists and acupuncturists who work in rural areas; however, large-sample studies are necessary to further verify results in the future.