Enlarged Perivascular Space and Index for Diffusivity Along the Perivascular Space as Emerging Neuroimaging Biomarkers of Neurological Diseases.

The existence of lymphatic vessels or similar clearance systems in the central nervous system (CNS) that transport nutrients and remove cellular waste is a neuroscientific question of great significance. As the brain is the most metabolically active organ in the body, there is likely to be a potential correlation between its clearance system and the pathological state of the CNS. Until recently the successive discoveries of the glymphatic system and the meningeal lymphatics solved this puzzle. This article reviews the basic anatomy and physiology of the glymphatic system. Imaging techniques to visualize the function of the glymphatic system mainly including post-contrast imaging techniques, indirect lymphatic assessment by detecting increased perivascular space, and diffusion tensor image analysis along the perivascular space (DTI-ALPS) are discussed. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index for of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders.

The burden of anemia among Chinese HIV-infected patients following the initiation of antiretroviral therapy in the treat-all era: a nationwide cohort study.

BACKGROUND: To assess the prevalence of anemia before and after antiretroviral therapy (ART) initiation and to identify impact of anemia on mortality among HIV-infected patients in China during the Treat-All era. METHODS: All HIV-infected patients who newly initiated ART between January 1, 2017 and December 31, 2020 were enrolled and followed up to December 31, 2021 in China. We analyzed the prevalence of anemia before and after ART initiation. Generalized estimating equations were fitted to determine factors associated with anemia after ART. Time-dependent cox proportional hazards models were performed to estimate the effect of anemia on death. RESULTS: Of 436,658 patients at the baseline of ART initiation, the overall prevalence of anemia was 28.6%. During a median 2.65 (IQR: 1.80-3.51) years of follow-up after ART initiation, 376,325 (86.2%) patients had at least one Hb measurement (a total of 955,300 hemoglobin measurements). The annual prevalence of anemia after ART was 17.0%, 14.1%, 13.4%, 12.6% and 12.7%, respectively. Being anemic at the baseline of ART initiation (adjusted odds ratio, aOR = 6.80, 95% confidence interval (CI): 6.67-6.92) was the strongest factor associated with anemia after ART. Anemia status after ART showed a strong association with death after multivariable adjustment (mild anemia: adjusted hazard ratio (aHR) = 2.65, 95% CI: 2.55-2.76; moderate anemia: aHR = 4.60; 95% CI:4.40-4.81; severe anemia: aHR = 6.41; 95% CI:5.94-6.91). CONCLUSIONS: In the era of ART universal access, pre-ART anemia was common among HIV-infected patients. Notably, a certain proportion of anemia still persisted after ART, and was significantly associated with death. We recommend strengthening the monitoring of patients at risk of anemia, especially in patients with baseline anemia or during the first year of ART, and timely treatment for correcting anemia.

The Human Immunodeficiency Virus Care Continuum in China: 1985-2015.

Background: Human immunodeficiency virus (HIV) care continuum attrition is a major global public health challenge. Few studies have examined this problem in resource-limited settings. We aimed to assess cumulative, current, and historical achievement along China's HIV continuum of care. Methods: A nationwide, serial cross-sectional study of all individuals with HIV infection diagnosed in China between 1 January 1985 and 31 December 2015 was conducted using data from China's HIV/AIDS information systems. Biennial estimates of the number of persons living with HIV were also used. We defined 7 steps in HIV care continuum as infected (estimated), diagnosed, linked, retained, enrolled, receiving antiretroviral therapy (ART), and virally suppressed. Cumulative, 30-year performance, and biennial performance during the most recent 10 years were examined. Results: A total of 573529 persons diagnosed with HIV infection were included. Cumulatively, 94% were linked, 88% were retained, 73% were enrolled, 67% were receiving ART, and 44% were suppressed. Greatest attrition was observed for adolescents, minorities, and those who reported injecting drug use as their route of infection. Improvement was observed from 2005 to 2015. As of the end of 2015, 68% among those infected were diagnosed, 67% among diagnosed were receiving ART, and 65% among those receiving ART were virally suppressed. After adjusting for those without viral load testing, the proportion suppressed increased to 89%. Conclusions: Despite dramatic improvements, China faces serious challenges in achieving the Joint United Nations Programme on HIV/AIDS 90-90-90 targets, because of substantial attrition along its continuum of HIV care.

Regional Challenges in the Prevention of Human Immunodeficiency Virus Drug Resistance.

In diverse global regions with significant human immunodeficiency virus (HIV) burden, programmatic, cultural, and provider-, patient-, and virus-related factors may result in HIV drug resistance, with global implications. This article reviews such common and unique challenges in Russia, Latin America and the Caribbean, China, and India, to suggest potential solutions.

Targeting HIV Prevention Based on Molecular Epidemiology Among Deeply Sampled Subnetworks of Men Who Have Sex With Men.

BACKGROUND: Molecular epidemiology can be useful in identifying clusters of human immunodeficiency virus (HIV) transmission that can be targeted for prevention. METHODS: Regular screening of 2000 men who have sex with men (MSM) in Beijing, China, for HIV infection every 2 months identified 179 primary infections (2007-2010). HIV-1 pol sequences were obtained and used to infer the transmission network and identify transmitted drug resistance (TDR) among these individuals. We evaluated the use of clinical and network information to target prevention efforts. Prevention efficiency was calculated as the number of infections saved per number of interventions. RESULTS: This cohort was infected with HIV-1 subtype B (28%), circulating recombinant form (CRF)_01 AE (53%), and CRF_07 BC (16%). The overall rate of TDR was low (5%), but the rate of clustering was high (64%), suggesting deep sampling of the subnetwork. Provision of a theoretically high-efficacy intervention like antiretroviral therapy to all participants had a prevention efficiency of 23%. The efficiency of targeting prevention based on lower CD4 counts (<200 cells/mL, <350 cells/mL, or <500 cells/mL) and higher viral loads (>100 000 copies/mL and >50 000 copies/mL) was between 10% and 18%. The efficiency of targeting prevention based on number of network connections was much higher (30%-42%). For example, treating the 33 participants with ≥5 connections in 2009 would have theoretically prevented 14 infections in 2010 (42% prevention efficiency). CONCLUSIONS: Regular HIV testing of MSM in Beijing can deeply sample the local transmission subnetwork, and targeting prevention efforts based on network connectivity may be an efficient way to deliver prevention interventions.

Cotrimoxazole prophylaxis and antiretroviral therapy: an observational cohort study in China.

OBJECTIVE: To assess if cotrimoxazole prophylaxis administered early during antiretroviral therapy (ART) reduces mortality in Chinese adults who are infected with human immunodeficiency virus (HIV). METHODS: We did a retrospective observational cohort study using data from the Chinese national free antiretroviral database. Patients older than 14 years who started ART between 1 January 2010 and 31 December 2012 and had baseline CD4+ T-lymphocyte (CD4+ cell) count less than 200 cells/µL were followed until death, loss to follow-up or 31 December 2013. Hazard ratios (HRs) for several variables were calculated using multivariate analyses. FINDINGS: The analysis involved 23 816 HIV-infected patients, 2706 of whom died during the follow-up. Mortality in patients who did and did not start cotrimoxazole during the first 6 months of ART was 5.3 and 7.0 per 100 person-years, respectively. Cotrimoxazole was associated with a 37% reduction in mortality (hazard ratio, HR: 0.63; 95% confidence interval, CI: 0.56-0.70). Cotrimoxazole in addition to ART reduced mortality significantly over follow-up lasting 6 months (HR: 0.65; 95% CI: 0.59-0.73), 12 months (HR: 0.58; 95% CI: 0.49-0.70), 18 months (HR: 0.49; 95% CI: 0.38-0.63) and 24 months (HR: 0.66; 95% CI: 0.48-0.90). The mortality reduction was evident in patients with baseline CD4+ cell counts less than 50 cells/µL (HR: 0.60; 95% CI: 0.54-0.67), 50-99 cells/µL (HR: 0.66; 95% CI: 0.56-0.78) and 100-199 cells/µL (HR: 0.78; 95% CI: 0.62-0.98). CONCLUSION: Cotrimoxazole prophylaxis started early during ART reduced mortality and should be offered to HIV-infected patients in low- and middle-income countries.

Population-based human immunodeficiency virus 1 drug resistance profiles among individuals who experienced virological failure to first-line antiretroviral therapy in Henan, China during 2010-2011.

BACKGROUND: In Henan, China, first-line antiretroviral treatment (ART) was implemented early in a large number of treatment-experienced patients who were more likely to have a drug resistance. Therefore, we investigated the human immunodeficiency virus (HIV)-1 drug resistance profiles among patients in Henan who experienced virological failure to ART. METHOD: A cross-sectional survey was administered in 10 major epidemic cities from May 2010 to October 2011. Adult patients who experienced virological failure (virus load ≥1,000 copies/mL) with >1 year of first-line antiretroviral treatment consented to provide blood for genotype resistance testing. The clinical and demographic data were obtained from the patients' medical records. Logistic regression analysis was performed to determine the factors associated with ≥1 significant drug resistance mutation. RESULTS: We included 3,235 patients with integral information and valid genotypic resistance data. The city, age, CD4 counts, virus load, treatment duration, and World Health Organization stage were associated with drug resistance, and 64.76% of patients acquired drug resistance. The nucleoside reverse transcriptase inhibitor (NRTI), non-(N)NRTI, and protease inhibitor resistance mutations were found in 50.26, 63.12, and 1.30% of subjects, respectively. Thymidine analogue mutations, NNRTI and even multidrug resistance complex were quite common in this patient cohort. CONCLUSION: Multiple and complex patterns of HIV-1 drug resistance mutations were identified among individuals who experienced virological failure to first-line ART in Henan, China during 2010-2011. Therefore, timely virological monitoring, therapy adjustments, and more varieties of drugs and individualized treatment should be immediately considered in this patient population.

[The prevalence and relevant factors of hyperglycemia in AIDS patients receiving antiretroviral therapy in a single center].

OBJECTIVE: To investigate the prevalence of hyperglycemia and its associated factors in AIDS patients receiving antiretroviral therapy (ART). METHODS: A cross-sectional survey was conducted to obtain the prevalence of hyperglycemia among AIDS patients in a single center. Univariate and multivariate non-conditional logistic regression analysis were used to determine influencing factors of hyperglycemia. RESULTS: A total of 504 AIDS patients participated in the survey, who have received ART for at least three months. The prevalence of hyperglycemia was 15.7%. Multivariate analysis showed that age (OR = 1.03, 95%CI 1.00-1.05), family history of diabetes (OR = 2.70, 95%CI 1.55-4.69), overweight (OR = 2.13, 95%CI 1.24-3.67), nadir CD4 cell counts 50-199 cells/µl (OR = 1.95, 95%CI 1.08-3.51) and less than 50 cells/µl (OR = 2.95, 95%CI 1.47-5.91) were relevant factors associated with hyperglycemia. CONCLUSIONS: Blood glucose should be monitored regularly in AIDS patients receiving ART , especially among patients with old age, family history of diabetes, overweight and nadir CD4 T cell counts less than 200 cells/µl.

Topological Electronic Transition Contributing to Improved Thermoelectric Performance in p-Type Mg3Sb2- xBix Solid Solutions.

Topological electronic transition is the very promising strategy for achieving high band degeneracy (NV) and for optimizing thermoelectric performance. Herein, this work verifies in p-type Mg3Sb2- xBix that topological electronic transition could be the key mechanism responsible for elevating the NV of valence band edge from 1 to 6, leading to much improved thermoelectric performance. Through comprehensive spectroscopy characterizations and theoretical calculations of electronic structures, the topological electronic transition from trivial semiconductor is unambiguously demonstrated to topological semimetal of Mg3Sb2- xBix with increasing the Bi content, due to the strong spin-orbit coupling of Bi and the band inversion. The distinct evolution of Fermi surface configuration and the multivalley valence band edge with NV of 6 are discovered in the Bi-rich compositions, while a peculiar two-step band inversion is revealed for the first time in the end compound Mg3Bi2. As a result, the optimal p-type Mg3Sb0.5Bi1.5 simultaneously obtains a positive bandgap and high NV of 6, and thus acquires the largest thermoelectric power factor of 3.54 and 6.93 µW cm-1 K-2 at 300 and 575 K, respectively, outperforming the values in other compositions. This work provides important guidance on improving thermoelectric performance of p-type Mg3Sb2- xBix utilizing the topological electronic transition.

Changing Mortality and Patterns of Death Causes in HIV Infected Patients - China, 2013-2022.

What is already known about this topic?: The advent of antiretroviral therapy (ART) has markedly decreased mortality rates among patients infected with human immunodeficiency virus (HIV). Globally, there has been a 43% reduction in acquired immunodeficiency syndrome (AIDS)-related deaths from 2010 to 2022. Additionally, prior research indicates that the initiation of ART at an early stage within China has substantially lowered mortality rates. What is added by this report?: Over the previous decade, following the implementation of China's universal ART access strategy, the patterns of mortality causes among HIV-infected individuals across the country have undergone significant alterations. In 2022, the all-cause mortality rate among this population was reported at 2.7%, with the non-AIDS-related mortality rate at 1.8%. However, it is important to consider that the accuracy of death reporting could contribute to potential misclassification of the underlying causes of death. What are the implications for public health practice?: Efforts to enhance health outcomes should persist in emphasizing the advancement of ART strategies, with a particular focus on mitigating non-AIDS-related mortality in the future.

Microsurgical Treatment of Arteriovenous Malformations: A Single-Center Study Experience.

OBJECTIVE: The purpose of the study was to assess the functional outcomes after microsurgical resection of arteriovenous malformations (AVMs) and to compare the results between patients eligible for A Randomized Trial of Unruptured Brain Arteriovenous Malformations in this surgical series to the results reported and the ARUBA study. METHODS: We reviewed the records of 169 patients who underwent microsurgical treatment of arteriovenous malformation (AVMs) in our institution between January 2016 and December 2021. These patients' functional status was assessed using modified Rankin Scale (mRS) scores at the last follow-up and before treatment. The mRS scores at the latest follow-up were classified into good outcomes (mRS < 3) and poor outcomes (mRS ≥ 3). Clinical presentation, patients' demographics, AVM characteristics, follow-up time, and obliteration rate were analyzed. Subgroup analyses were performed on the whole cohort, comparing Spetzler-Martin Grade I and Grade II, and ARUBA-eligible AVMs. RESULTS: The initial hemorrhagic presentation occurred in 71 (42%) out of 169 patients. The majority of the patients presented with headaches (73%). The AVMs were completely obliterated in 166 (98.2%) patients. The series included 65 Spetzler-Martin Grade I (38.5%), 46 Grade II (27.2%), 32 Grade III (18.9%), 22 Grade IV (13%), and 4 Grade V (2.4%) AVMs. There were 98 unruptured and 79 ARUBA-eligible cases. Also, optimal functional outcome was achieved in 145 (85.8%) patients. The overall mortality rate was 5.3% (9/169). The multivariate analysis illustrated that a poor outcome was significantly associated with presurgical mRS ≥3 (p < 0.013; OR, 0.206; 95% CI 0.059-0.713), increasing age (p < 0.045; odds ratio [OR], 1.022; 95% CI 1.000-0.045), and female gender (p < 0.009; OR, 2.991; 95% CI 1.309-6.832). CONCLUSIONS: Our study suggests that better outcomes can be obtained using microsurgical resection in the majority of patients with AVMs. Independent predictors of poor outcomes after surgical resection of AVMs include increasing age at the time of surgery, poor presurgical functional status, and female gender. Supposing that patients are more suitable for microsurgery after presurgical examination, outcomes are normally better in that case than those achieved by multimodal interventions (such as conservative treatment or ARUBA treatment arm). Therefore, we recommend early surgical removal on all surgically accessible AVMs to prevent successive hemorrhages and the consequences of poor neurological outcomes.

Epidemiological trends of severely immunosuppressed people living with HIV at time of starting antiretroviral treatment in China during 2005-2018.

OBJECTIVES: High HIV-related mortality is mainly associated with severe immunosuppression (CD4 count < 50 cells/µL) in people living with HIV (PLWH). This study intended to explore the trends in epidemic and early mortality among PLWH with severe immunosuppression for further targeted intervention. METHODS: We extracted the data of treatment-naïve PLWH with severe immunosuppression from China's National Free Antiretroviral Treatment (ART) Program database. Early mortality (within 6 or 12 months after initiating ART) and spatial, temporal, and population distribution were analyzed during 2005-2018. RESULTS: Of 748,066 treatment-naïve PLWH, 105,785 (14.1%) were severely immunosuppressed PLWH aged more than 15-year-old. The proportion of severely immunosuppressed PLWH peaked at 31.4% and then decreased with time, leveling off at approximately 11-12% from 2015 onward. Early mortality rates of these PLWH declined significantly (from 17.0% to 8.1% after 6 months of initiating ART; 20.4% to 10.6% after 12 months; both p values < 0.01) from 2005-2007 to 2016-2018. In the South-central and Southwest, the number of these PLWH was larger than that in the other regions during 2005-2018, and it increased to 4780 (37.1%) and 3370 (26.2%) in 2018. The proportion of PLWH aged 30-44 years among all treatment-naïve severely immunosuppressed PLWH in each region was higher than that of other age groups during 2005-2018. After the proportion decreased during 2005-2007, the proportion of PLWH aged 45-59 years in Southwest and South-central were increased steadily from 11% (69/626) and 16.7% (358/2140) in 2007 to 33.8% (1138/3370) and 34.0% (1626/4780) in 2018, respectively; the proportion of PLWH aged ≥60 years showed an increasing trend during 2005-2018; while changes in the proportion of those age groups were less pronounced in North and Northeast. The proportion of PLWH infected by heterosexual contact was high at 83% (2798/3370) in Southwest, and 75.1% (3588/4780) in South-central in 2018; conversely, proportion of PLWH infected by homosexual contacts was largest in North (57.8% [500/865]) and Northeast (59.9% [561/936]). CONCLUSIONS: The persistent burden of treatment-naïve PLWH with severe immunosuppression remains challenging. Our results provide evidence for policy-makers to allocate resources and establish targeting strategies to identify early infection of PLWH.

A Novel Sushi-IL15-PD1 CAR-NK92 Cell Line With Enhanced and PD-L1 Targeted Cytotoxicity Against Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with a limited response to current therapies. Novel and effective treatment is urgently needed. Herein, a chimeric antigen receptor (CAR)-NK92 cell line, with an interleukin (IL)-15Rα-sushi/IL-15 complex and a Programmed cell death-1(PD1) signal inverter was constructed and named SP ( S ushi-IL15- P D1). We showed that CAR expression enabled SP cells to proliferate independently of IL-2 and became more resistant to nutrition starvation-induced apoptosis. Meanwhile, SP cells were more effective than NK92 in PDAC cell killing assays in vitro and in vivo, and there was a positive correlation between the killing capability of SP cells and PD-L1 expression in pancreatic cancer cells. Based on the synergistic and comprehensive effects of the special CAR structure, the adhesion, responsiveness, degranulation efficiency, targeted delivery of cytotoxic granule content, and cytotoxicity of SP cells were significantly stronger than those of NK92. In conclusion, the SP cell line is a promising adoptive immunotherapy cell line and has potential value as an adjuvant treatment for pancreatic cancer, especially in patients with high PD-L1 expression.

Clinical analysis of skin lesions in 796 Chinese HIV- positive patients.

Skin lesions are often associated with human immunodeficiency virus (HIV) infection, reflecting the immunocompromised status of the individual. We investigated the relationship between skin lesions and immune function in a retrospective study of 796 Chinese HIV patients with and without highly active antiretroviral therapy (HAART). Of the 651 patients who had not received HAART, we found that 531 (81.6%) had apparent skin lesions. The incidence of infectious skin diseases (fungi, viruses, bacteria, spirochetes and parasites) and non-infectious skin diseases (excluding skin cancer) was 68.8% and 34.9%, respectively. Mean CD4(+) T-cell counts and CD4(+)/CD8(+) ratios were lower in patients with skin lesions than in patients without lesions (178 ± 96/µl vs. 306 ± 189/µl (p < 0.05) and 0.22 vs. 0.34 (p < 0.01), respectively). Candidiasis (25.8%), eczema (19.2%), nodular prurigo (13.8%), dermatophyte infections (10.6%) and herpes zoster (9.4%) were most common in Chinese patients with HIV. Among the 145 patients who had started HAART, there was a significantly lower prevalence of skin diseases (29.0%), although drug eruptions (12.4%) were more commonly observed. These findings indicate that HAART often reduces the incidence of infectious and non-infectious skin lesions in patients with HIV, but can itself be the cause of drug eruptions.

MEX3A contributes to development and progression of glioma through regulating cell proliferation and cell migration and targeting CCL2.

Glioma is one of the most commonly diagnosed intracranial malignant tumors with extremely high morbidity and mortality, whose treatment was seriously limited because of the unclear molecular mechanism. In this study, in order to identify a novel therapeutic target for glioma treatment, we explored the functions and mechanism of MEX3A in regulating glioma. The immunohistochemical staining of MEX3A in glioma and normal tissues revealed the upregulation of MEX3A and further indicated the relationship between high MEX3A expression and higher malignancy as well as poorer prognosis of glioma. In vitro loss-of-function and gain-of-function experiments comprehensively demonstrated that MEX3A may promote glioma development through regulating cell proliferation, cell apoptosis, cell cycle, and cell migration. In vivo experiments also suggested the inhibition of glioma growth by MEX3A knockdown. Moreover, our mechanistic study identifies CCL2 as a potential downstream target of MEX3A, which possesses similar regulatory effects on glioma development with MEX3A and could attenuate the promotion of glioma induced by MEX3A overexpression. Overall, MEX3A was identified as a potential tumor promoter in glioma development and therapeutic target in glioma treatment.

Immune restoration in HIV-1-infected patients after 12 years of antiretroviral therapy: a real-world observational study.

Using normalization of CD4 counts as the main evaluation parameter of complete immune restoration for HIV-1 patients under antiretroviral therapy (ART) might be not enough. A comprehensive evaluation system more accurately reflecting immune restoration are urgently needed. Totally, 91,805 HIV-1 patients from 17 tertiary hospitals in China during 2005-2018 were included in this study. Immune restoration and mortality were assessed. Patients initiated ART with baseline CD4 counts <50, 50-199, 200-349, 350-499, and ≥500 cells/µL, and results showed an increase in the median CD4 counts to 445 (12-year), 467 (12-year), 581 (11-year), 644 (7-year), and 768 cells/µL (5-year), as well as the CD4/CD8 ratio to 0.59 (12-year), 0.65 (12-year), 0.79 (11-year), 0.82 (7-year), 0.9 (5-year), respectively. The median CD8 count was relatively high (median range 732-845 cells/µL), regardless of the baseline CD4 counts. Furthermore, the probabilities of death in patients achieving CD4 counts ≥500 cells/µL and CD4/CD8 ratio ≥0.8 simultaneously were significantly lower than those in patients achieving either CD4 counts ≥500 cells/µL (2.77% vs 3.50%, p=0.02) or CD4/CD8 ≥ 0.8 (2.77% vs 4.28%, p<0.001) after 12-year of ART. In this study, a new binary-indicator would accurately assess immune restoration in the era of "treat all."

Mitochondrial DNA base excision repair and mitochondrial DNA mutation in human hepatic HuH-7 cells exposed to stavudine.

The mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTIs) is due to the inhibition of mitochondrial DNA (mtDNA) polymerase gamma (Pol gamma), resulting in a blockade of mtDNA replication and subsequent disruption of cellular energetics. Because mtDNA Pol gamma is not only involved in mtDNA replication but also responsible for mtDNA repair, we hypothesize that mitochondrial oxidative stress leads to changes in the balance between mtDNA repair and mutation following stavudine (d4T) treatment. However, the mechanisms underlying how changes in mtDNA base excision repair (mtBER) lead to mtDNA mutation remain unclear. To test this hypothesis, total mitochondrial repair capability, different steps of mtBER, mtDNA mutations in D-loop, and oxidative stress were all assessed in cultured HuH-7 human hepatoblast cells treated with d4T for 2 weeks. Assessment by denaturing Southern blotting and quantitative PCR revealed that d4T significantly reduced in vivo repair of H(2)O(2) damaged mtDNA in HuH-7 cells. d4T reduced total in vitro mtBER and DNA Pol gamma capability, but did not affect mtDNA oxoguanine glycosylase and apurinic/apyrimidinic endonuclease activity in HuH-7 cells. In addition, d4T treatment is associated with a significant increase in the frequency of mtDNA mutations in HuH-7 cells. In conclusion, d4T treatment reduces mtBER and contributes mechanistically to NRTI-induced mtDNA mutation. These events may potentially be associated with some diseases linked to mtDNA mutation.

Gender Differences in Outcomes of Antiretroviral Treatment Among HIV-Infected Patients in China: A Retrospective Cohort Study, 2010-2015.

BACKGROUD: Women now account for about half of all people living with HIV worldwide, but researchers lack clear information and large population-based study about gender differences in treatment outcomes. METHODS: A nationwide retrospective observational cohort study with data from the China National Free Antiretroviral Treatment Program was performed. Antiretroviral-naive patients older than 18 years initiating standard antiretroviral therapy between January 1, 2010, and December 31, 2011, were included and followed up to December 31, 2015. We used modified Poisson regression models to estimate the impact of gender on virological suppression and retention in treatment, and Kaplan-Meier analysis and Cox proportional hazard models to evaluate gender difference in mortality. RESULTS: Sixty-eight thousand six hundred forty-six patients [46,083 (67.1%) men and 22,563 (32.9%) women] with HIV met eligibility criteria. Women were significantly more likely to achieve virological suppression than men both at 12 months [adjusted relative risk (aRR) 1.02, 95% confidence interval (CI): 1.01 to 1.03, P < 0.001] and 48 months (aRR 1.01, 95% CI: 1.00 to 1.02, P = 0.005) after initiating antiretroviral treatment. Women were also more likely to remain in treatment at 12 months (aRR 1.02, 95% CI: 1.01 to 1.02, P < 0.001) and 48 months (aRR 1.04, 95% CI: 1.03 to 1.05, P < 0.001), although the difference became insignificant in alive patients. All-cause mortality was lower in women than in men (2.34 vs. 4.03 deaths/100PY, adjusted hazard ratio 0.72, 95% CI: 0.67 to 0.77, P < 0.001). CONCLUSIONS: In China, women are more likely to achieve virological suppression, remain in treatment, and have a significantly lower risk of death than men. Future studies could take both biological and sociobehavioral factors into analysis to clarify the influence factors.

Comparing Outcomes of HIV-Infected Chinese Adults on Antiretroviral Therapy by CD4 Count at Treatment Initiation: A Nationwide Retrospective Observational Cohort Study, 2012-2014.

The chief concerns for antiretroviral therapy (ART) programs considering removal of CD4+ cell count thresholds for treatment are the increased incidence of ART-related adverse events. A nationwide observational cohort study was conducted among patients who initiated ART in 2012. We divided the eligible patients into three groups: an early ART group with a baseline CD4+ cell count of 500 cells/µL or greater, a standard ART group with a baseline CD4+ cell count between 350 and 499 cells/µL, and a late ART group with a baseline CD4+ cell count between 200 and 349 cells/µL. These patients were followed up to December 31, 2014 and observed for three outcomes: virological failure, treatment nonretention, or time to death. Patients who met the eligibility criteria numbered at 26,752. Out of all study participants, 20,827 participants were in late ART group, 4336 were in standard ART group, and 1589 were in early ART group. Patients in late ART group were more likely to become virally suppressed 12 and 24 months after treatment initiation than patients in early ART group [adjusted odds ratio (aOR) 0.81; 95% CI, 0.69-0.95 and aOR, 0.78; 95% CI, 0.65-0.94]. Treatment nonretention was also less likely to occur among patients in late ART group than early ART group 12 months after treatment initiation (aOR, 0.85; 95% CI, 0.75-0.96). Compared with early ART group, neither standard ART group nor late ART group had a statistically significant difference in the time-to-death analysis. Late ART initiates were more likely to be virally suppressed and retained on treatment than early ART initiates. The importance of treatment retention and adherence should be emphasized for high CD4+ patients newly initiated to ART therapy through education and counseling programs.

Growth of HIV-Infected Children in the Early Stage of Antiretroviral Treatment: A Retrospective Cohort Study in China.

Malnutrition and human immunodeficiency virus (HIV)-related complications are commonly seen in HIV-infected children, and these have been shown in high-prevalent areas such as Africa. Antiviral therapy (ART) has notably controlled disease progression, whereas it effectively reverses underweight and growth retardation in HIV-infected children. This study was conducted to evaluate the growth status after initiation of ART in HIV-infected children in China. A retrospective cohort study was conducted based on the National Science and Technology Major Project. HIV-infected children who initiated antiretroviral treatment between January 1st, 2012 and December 31st, 2012 were followed up to December 31st, 2014. Z-scores of height and weight were calculated by WHO Anthro (plus). Linear mixed-effects models were used to model trajectories of weight- and height-for-age Z-scores. Seven hundred forty-four participants enrolled in the study, with 585 participants and 712 participants who had WAZ (weight-for-age Z-score) and HAZ (height-for-age Z-score), respectively, before initiation of ART. Among them, 125 (21.4%) were underweight and 301 (42.3%) were stunted. After treatment, among the 125 underweight children, WAZ improved in 69 patients, regained more than -2 on average. Among the 301 stunted children, HAZ improved in 123 patients, regained more than -2 on average. WAZ improved for the first 6 months by 0.052 units each month and then stabilized, whereas HAZ consistently improved by 0.014 units each month over time. Antiretroviral treatment reversed the adverse effects of HIV to some degree. Early diagnosis and treatment, with an effective nutrition program, is necessary to improve malnutrition further.