Effects of Prolonged Administration of Tenofovir Disoproxil Fumarate-Containing Antiviral Regimen on Renal Function in Low-Risk of Kidney Injury HIV Patients.

This study intended to investigate the impact of long-term tenofovir fumarate (TDF) antiviral regimen on renal function in human immunodeficiency virus (HIV)-infected patients with low-risk of kidney injury. The observational study involving 100 HIV-infected patients without underlying diseases who achieved virological suppression and immunological recovery after sustained antiviral regimen of TDF+ lamivudine+ efavirenz (TLE) for 3.19 years. Renal function, including estimated glomerular filtration rate (eGFR), blood and urine ß2 microglobulin, and other parameters, was assessed every 3 months over a period of 2.5 years. The eGFR showed a slight increasement from 116.0 at month 0 to 119.7 at month 30. Blood ß2 microglobulin increased from 2.02 mg/L at month 0 to 2.77 mg/L at month 30. Compared to month 0, the difference in blood ß2 microglobulin was statistically significant at month 6 and months 12-30 (P < .05). The incidence of proximal renal tubular dysfunction fluctuated from 2% at month 0 to 2.5% at month 30. The urine ß2 microglobulin fluctuated from 0.5 (0.3-1.1) to 0.8 (0.5-1.35) mg/L at months 18-30, which was higher than 0.41 (0.18-1.1) mg/L at month 0 (P < .05). The abnormal concentration proportion of urine ß2 microglobulin fluctuated from 72.7% to 81.3% at months 18-30, which was higher than the proportion of 57.0% at month 0. The abnormal proportion of blood ß2 microglobulin, urine ß2 microglobulin, and proximal renal tubular dysfunction were not correlated with eGFR (r1 = 0.119, r2 = -0.008, r3 = -0.165, P > .05). Long-term TDF antiviral regimen in low-risk of kidney injury HIV-infected patients may lead to damage in the proximal renal tubules and glomeruli. Blood and urine ß2 microglobulin levels may be helpful in screening for renal dysfunction.

Tolerability and effectiveness of albuvirtide combined with dolutegravir for hospitalized people living with HIV/AIDS.

Treatment options for hospitalized people living with HIV/AIDS (PLWHA) with opportunistic infections and comorbidities are limited in China. Albuvirtide (ABT), a new peptide drug, is a long-acting HIV fusion inhibitor with limited drug-drug interactions and fast onset time. This single-center, retrospective cohort study investigated the effectiveness and safety of ABT plus dolutegravir (DTG) therapy in a real-world setting. We performed a chart review on the electronic patient records for hospitalized PLWHA using ABT plus DTG between April and December 2020. The clinical outcomes were retrospectively analyzed. Among 151 PLWHA (mean age 47.6 ± 15.9 years), 140 (93%) had at least 1 episode of bacterial and/or fungal infections and 64 (42%) had other comorbidities including syphilis, hepatitis B, and/or hypertension. ABT plus DTG was given to 87 treatment-naïve (TN) and 64 treatment-experienced (TE) PLWHA. Regardless of treatment history, mean HIV-1 RNA levels significantly decreased from 4.32 log10copies/mL to 2.24 log10copies/mL, 2.10 log10copies/mL and 1.89 log10copies/mL after 2, 4 and 8 weeks of treatment, respectively (P < .0001). Compared with baseline mean CD4 + T-cell counts of 122.72 cells/µL, it increased to 207.87 cells/µL (P = .0067) and 218.69 cells/µL (P = .0812) after 4 and 8 weeks of treatment. Except for limited laboratory abnormalities such as hyperuricemia, increased creatinine level, and hyperglycemia observed after treatment, no other clinical adverse events were considered related to ABT plus DTG. Data suggests that ABT plus DTG is safe and effective for critically-ill hospitalized PLWHA. In view of the rapid viral load suppression and restoration of CD4 + count within 8 weeks of treatment, its clinical application warrants further investigation.

Ancient genomes reveal millet farming-related demic diffusion from the Yellow River into southwest China.

The study of southwest China is vital for understanding the dispersal and development of farming because of the coexistence of millet and rice in this region since the Neolithic period.1,2 However, the process of the Neolithic transition in southwest China is largely unknown, mainly due to the lack of ancient DNA from the Neolithic period. Here, we report genome-wide data from 11 human samples from the Gaoshan and Haimenkou sites with mixed farming of millet and rice dating to between 4,500 and 3,000 years before present in southwest China. The two ancient groups derived approximately 90% of their ancestry from the Neolithic Yellow River farmers, suggesting a demic diffusion of millet farming to southwest China. We inferred their remaining ancestry to be derived from a Hòabìnhian-related hunter-gatherer lineage. We did not detect rice farmer-related ancestry in the two ancient groups, which indicates that they likely adopted rice farming without genetic assimilation. We, however, observed rice farmer-related ancestry in the formation of some present-day Tibeto-Burman populations. Our results suggested the occurrence of both demic and cultural diffusion in the development of Neolithic mixed farming in some parts of southwest China.

Paleoproteomic evidence reveals dairying supported prehistoric occupation of the highland Tibetan Plateau.

The extreme environments of the Tibetan Plateau offer considerable challenges to human survival, demanding novel adaptations. While the role of biological and agricultural adaptations in enabling early human colonization of the plateau has been widely discussed, the contribution of pastoralism is less well understood, especially the dairy pastoralism that has historically been central to Tibetan diets. Here, we analyze ancient proteins from the dental calculus (n = 40) of all human individuals with sufficient calculus preservation from the interior plateau. Our paleoproteomic results demonstrate that dairy pastoralism began on the highland plateau by ~3500 years ago. Patterns of milk protein recovery point to the importance of dairy for individuals who lived in agriculturally poor regions above 3700 m above sea level. Our study suggests that dairy was a critical cultural adaptation that supported expansion of early pastoralists into the region's vast, non-arable highlands, opening the Tibetan Plateau up to widespread, permanent human occupation.

Human genetic history on the Tibetan Plateau in the past 5100 years.

Using genome-wide data of 89 ancient individuals dated to 5100 to 100 years before the present (B.P.) from 29 sites across the Tibetan Plateau, we found plateau-specific ancestry across plateau populations, with substantial genetic structure indicating high differentiation before 2500 B.P. Northeastern plateau populations rapidly showed admixture associated with millet farmers by 4700 B.P. in the Gonghe Basin. High genetic similarity on the southern and southwestern plateau showed population expansion along the Yarlung Tsangpo River since 3400 years ago. Central and southeastern plateau populations revealed extensive genetic admixture within the plateau historically, with substantial ancestry related to that found in southern and southwestern plateau populations. Over the past ~700 years, substantial gene flow from lowland East Asia further shaped the genetic landscape of present-day plateau populations. The high-altitude adaptive EPAS1 allele was found in plateau populations as early as in a 5100-year-old individual and showed a sharp increase over the past 2800 years.

Maternal genetic history of ancient Tibetans over the past 4,000 years.

The settlement of the Tibetan Plateau epitomizes human adaptation to a high-altitude environment that poses great challenges to human activity. Here, we reconstruct a 4,000-year maternal genetic history of Tibetans using 128 ancient mitochondrial genome data from 37 sites in Tibet. The phylogeny of haplotypes M9a1a, M9a1b, D4g2, G2a'c, and D4i show that ancient Tibetans shared the most recent common ancestor (TMRCA) with ancient Middle and Upper Yellow River populations around the Early and Middle Holocene. In addition, the connections between Tibetans and Northeastern Asians varied over the past 4,000 years, with a stronger matrilineal connection between the two during 4,000-3,000 BP, and a weakened connection after 3,000 BP, that were coincident with climate change, followed by a reinforced connection after the Tubo period (1,400-1,100 BP). Besides, an over 4,000-year matrilineal continuity was observed in some of the maternal lineages. We also found the maternal genetic structure of ancient Tibetans was correlated to the geography and interactions between ancient Tibetans and ancient Nepal and Pakistan populations. Overall, the maternal genetic history of Tibetans can be characterized as a long-term matrilineal continuity with frequent internal and external population interactions that were dynamically shaped by geography, climate changes, as well as historical events.

[Genetic Subtypes and Status of Transmitted Drug Resistance of HIV/AIDS Patients in Sichuan].

Objective: To investigate the distribution characteristics of the HIV genetic subtypes and the status quo of transmitted drug resistance among HIV/AIDS patients in Sichuan with no previous history of receiving antiretroviral therapy (ART). Methods: Adult HIV/AIDS patients who were hospitalized in Sichuan and who had no previous history of exposure to ART drugs exposure were enrolled. In-house sequencing of the HIV gene was done and phylogenetic tree was constructed to analyze the HIV genetic subtypes. The Stanford HIV drug resistance database was used to make online comparison of the drug resistance mutation sites and to determine the presence or absence of drug resistance, and the type and level of drug resistance. Results: A total of 120 patients were enrolled for the study, and 120 blood samples were collected. The genetic subtypes of 87.5% (105/120) of the samples were successfully amplified. The distribution characteristics of HIV genotype were as follows, CRF01_AE accounted for 46.67% (49/105), CRF07_BC accounted for 39.05% (41/105), and the others genetic subtypes, 14.28% (15/105). There were no significant differences between the different genetic subtypes in sex, age, ethnicity, HIV transmission route, drug resistance, baseline HIV RNA and baseline CD4 ( P>0.05). Drug-resistant mutation sites were detected in 25 samples, accounting for 20.83% (25/120) of all samples, with 16.67% (20/120) being potential drug resistance and 4.17% (5/120) being transmitted drug resistance. For the 24 samples found to be resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs), the mutation frequency of V179D/E was the highest. One patient showed resistance to protease inhibitors (PI) and the mutation site was M46I. No nucleoside reverse transcriptase inhibitor (NRTI) or integrase inhibitors (INTI) resistance were found. Conclusions: The main genetic subtypes of HIV/AIDS patients in Sichuan with no previous history of receiving ART were CRF01_AE and CRF07_BC. The incidence of transmitted drug resistance was low. The drug resistance detected in the study was predominantly resistance to NNRTIs. Baseline HIV drug resistance testing is of great significance for formulating effective ART regimens.

Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe COVID-19: a randomised clinical trial.

BACKGROUND: There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. To compare the effectiveness of a novel genetically engineered recombinant super-compound interferon (rSIFN-co) with traditional interferon-alpha added to baseline antiviral agents (lopinavir-ritonavir or umifenovir) for the treatment of moderate-to-severe COVID-19. METHOD: In this multicenter randomized (1:1) trial, patients hospitalized with moderate-to-severe COVID-19 received either rSIFN-co nebulization or interferon-alpha nebulization added to baseline antiviral agents for no more than 28 days. The primary endpoint was the time to clinical improvement. Secondary endpoints included the overall rate of clinical improvement assessed on day 28, the time to radiological improvement and virus nucleic acid negative conversion. RESULTS: A total of 94 patients were included in the safety set (46 patients assigned to rSIFN-co group, 48 to interferon-alpha group). The time to clinical improvement was 11.5 days versus 14.0 days (95% CI 1.10 to 2.81, p = .019); the overall rate of clinical improvement on day 28 was 93.5% versus 77.1% (difference, 16.4%; 95% CI 3% to 30%); the time to radiological improvement was 8.0 days versus 10.0 days (p = .002), the time to virus nucleic acid negative conversion was 7.0 days versus 10.0 days (p = .018) in the rSIFN-co and interferon alpha arms, respectively. Adverse events were balanced with no deaths among groups. CONCLUSIONS AND RELEVANCE: rSIFN-co was associated with a shorter time of clinical improvement than traditional interferon-alpha in the treatment of moderate-to-severe COVID-19 when combined with baseline antiviral agents. rSIFN-co therapy alone or combined with other antiviral therapy is worth to be further studied.Key messagesThere are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus.In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir-ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents.

The KATP channel opener, nicorandil, ameliorates brain damage by modulating synaptogenesis after ischemic stroke.

With population growth and aging, more and more patients with cerebral infarction have varying degrees of disability. ATP-sensitive potassium (KATP) channels regulate many cellular functions by coupling metabolic status with cell membrane electrical activity. Nicorandil (N-(2-hydroxyethyl)-nicotinamide nitrate) is the first KATP channel opener approved for clinical use. It has been reported that it might exert protective effects on the cerebral infarction by increasing cerebral blood flow and reducing inflammation. However, only a few studies explored its role in synaptogenesis. We made the rat model of middle cerebral artery occlusion (MCAO). Nicorandil was administered to rats via oral administration immediately after the surgery at a dose of 7.5 mg/kg and then daily for the next days. Infarct volume, cerebral edema, neurological deficits, cognitive impairment, and the level of Synaptophysin (SYP)、Growth associated protein-43 (GAP43) and neuronal nuclear antigen (NeuN) levels were measured to evaluate the effect of nicorandil. Our data showed that nicorandil treatment could decrease brain damage, improve learning and memory, and increase SYP、GAP43 and NeuN level. Taken together, we propose that nicorandil, as an opener of the KATP channel, provides a neuroprotective role in MCAO by promoting synaptic connections.

Caudal paramedian midbrain infarction: a clinical study of imaging, clinical features and stroke mechanisms.

Caudal paramedian midbrain infarction (CPMI) is an extremely rare form of ischemic stroke and related clinical studies are scarce. Our aim is to investigate the clinical features, neuroradiological findings and stroke etiology of CPMI. We conducted a retrospective study of 12 patients with CPMI, confirmed by diffusion-weighted MRI from 6820 cerebral infarction patients at our stroke center from January 2012 to August 2018. Experienced neurologists evaluated the clinical manifestations, neuroimaging findings and stroke mechanisms. Twelve patients (11 men, 1 woman) aged 42-81 years old met the study inclusion criteria. Seven patients had a unilateral infarction (two right-sided, five left-sided) and five had bilateral infarctions. Sagittal image showed a backward oblique sign in the lower level of the midbrain. Significantly, the bilateral CPMIs presented with a characteristic "V-shaped" appearance in the axial MRI. All patients presented with bilateral cerebellar dysfunction which included dysarthric speech, truncal or gait ataxia and four-limb ataxia. In addition, diplopia and internuclear ophthalmoplegia were frequently encountered in CPMI. Five (41.7%) patients were classified with large artery atherosclerosis, four (33.3%) with small vessel disease, two (16.7%) with cardiogenic embolism, and one (8.3%) with undetermined etiology. CPMI is a rare cerebrovascular disease that destroys the Wernekink commissure, medial longitudinal fasciculi and other adjacent structures. It is characterized by bilateral cerebellar ataxia and eye movement disorders, mainly internuclear ophthalmoplegia. A distinct "V-shaped" radiological feature can be seen in bilateral CPMI patients. The primary mechanisms of unilateral CPMI involve small vessel disease. The underlying stroke mechanisms of bilateral CPMI are either large artery atherosclerosis disease or cardiac embolism.

Author Correction: Winter-to-summer seasonal migration of microlithic human activities on the Qinghai-Tibet Plateau.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluation of Clinical Features and Stroke Etiology in Patients with Bilateral Middle Cerebellar Peduncle Infarction.

OBJECTIVE: The aim of this study was to characterize clinical features, etiologies, and mechanisms of strokes due to bilateral middle cerebellar peduncle infarction (BMCPI). METHODS: Cases diagnosed as BMCPI in our hospital were retrieved, and a literature review was performed. Data on clinical features and brain MRI were obtained. Extracranial and intracranial segments of the vertebrobasilar artery were assessed by using digital subtraction angiography, magnetic resonance angiography, or computed tomography angiography. RESULTS: Thirteen cases (11 men and 2 women) of BMCPI were identified. A high-intensity signal of diffusion-weighted imaging sequence involving the bilateral middle cerebellar peduncle was observed in all patients. Most patients experienced vertigo, dysarthria, ataxia, and hearing disorders. Eleven of these cases were classified as large artery atherosclerosis, one as traumatic vertebral artery (VA) dissection, and one as giant cell arteritis. CONCLUSION: BMCPI is a rare cerebrovascular disease characterized by vertigo, ataxia, and dysarthria, which may also be accompanied by a hearing deficit or clinical signs of brainstem damage. BMCPI may be associated with hypoperfusion secondary to occlusive disease of the bilateral VA or proximal basilar artery.

Winter-to-summer seasonal migration of microlithic human activities on the Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau (QTP) has become a valuable site for investigation of adaptive regimes of prehistoric humans to extreme environments. At present most studies have focused solely on a single site. Using a more integrated approach that covers the complete scope of the plateau is needed to better understand the expansion logic of prehistoric humans moving towards the plateau. Here, we conducted accelerator mass spectrometry 14C dating of two microlithic sites. Canxiongashuo (CXGS) and Shalongka (SLK), which are located at the inner and marginal areas of the QTP, respectively. By using geographic information system, literature, and natural environmental factors, we constructed a model for the relationship between traveling distance and time, and we also used these factors to construct a plateau environmental index. The results indicated that the ages of the CXGS and SLK sites are 8.4-7.5 cal. ka BP and 8.4-6.2 cal. ka BP, respectively. Combining the archaeological evidence and literature, hunter-gatherers may have seasonal migration activities at low altitude in winter and high altitude in summer in order to make full use of natural resources. Our model of relationship between traveling distance and time shows that hunter-gatherers in CXGS site was active on the plateau all year-round at approximately 8.3 cal. ka BP. According to EI and archaeological remains, we propose that SLK site was a winter camp of prehistoric hunter-gatherers. Taken together, we determined 8.4-6.0 cal. ka BP as a transitional period from the Paleolithic to Neolithic Ages, and winter camps of hunter-gatherers evolved into settlements in the Neolithic Age.

Ancient mitogenomes show plateau populations from last 5200 years partially contributed to present-day Tibetans.

The clarification of the genetic origins of present-day Tibetans requires an understanding of their past relationships with the ancient populations of the Tibetan Plateau. Here we successfully sequenced 67 complete mitochondrial DNA genomes of 5200 to 300-year-old humans from the plateau. Apart from identifying two ancient plateau lineages (haplogroups D4j1b and M9a1a1c1b1a) that suggest some ancestors of Tibetans came from low-altitude areas 4750 to 2775 years ago and that some were involved in an expansion of people moving between high-altitude areas 2125 to 1100 years ago, we found limited evidence of recent matrilineal continuity on the plateau. Furthermore, deep learning of the ancient data incorporated into simulation models with an accuracy of 97% supports that present-day Tibetan matrilineal ancestry received partial contribution rather than complete continuity from the plateau populations of the last 5200 years.

Effects of long-term exposure to tenofovir disoproxil fumarate-containing antiretroviral therapy on renal function in HIV-positive Chinese patients.

BACKGROUND: The regimen containing tenofovir disoproxil fumarate (TDF)+lamivudine or emtricitabine + efavirenz remains the recommended first-line antiretroviral therapy (ART) by the WHO. Limited studies, however, have been conducted on the incidence of renal impairment among Chinese patients with long-term exposure to TDF-containing ART regimens. METHODS: We retrospectively analyzed 269 eligible patients who had no comorbidities and received TDF-containing ART from July 2014 to April 2015. TDF-related renal impairment was defined as a decrease of eGFR by >25% from baseline or eGFR <90 ml/min/1.73 m2. Decreased renal function was defined as a decrease of eGFR by > 10 mL/min/1.73 m2 from baseline. RESULTS: 97.0% of study patients were male (median age 29, eGFR 124.0 ml/min/1.73 m2). After 168-week of ART, renal impairment occurred in 7 patients (2.7%). The incidence of decreased renal function was significantly higher at Week 168 compared with that observed at Week 12 (24.8% vs 3.7%, p < 0.001). In generalized estimating equation analysis, patients receiving ART for 144-week (aOR4.1, 95%CI 2.0-8.4) and 168-week (aOR8.4, 95%CI 4.2-16.4) were more likely to develop decreased renal function compared with those receiving ART for 12-week, so were the patients with a weight <58 kg (aOR2.3, 95%CI 1.2-4.3) and 58-66 kg (aOR2.0, 95%CI 1.0-3.8) compared to those with a weight ≥67 kg. At 168-week, 41.0% of 100 patients examined had elevated urine ß2-microglobulin levels, which were negatively correlated with eGFR (r = -0.22, p = 0.02). CONCLUSIONS: TDF-related renal impairment remained rare in HIV-positive Chinese patients with a median age of 29 years who had no comorbidities. A lower weight and duration of ART were associated with decreased renal function.

Prediction model for the efficacy of folic acid therapy on hyperhomocysteinaemia based on genetic risk score methods.

No risk assessment tools for the efficacy of folic acid treatment for hyperhomocysteinaemia (HHcy) have been developed. We aimed to use two common genetic risk score (GRS) methods to construct prediction models for the efficacy of folic acid therapy on HHcy, and the best gene-environment prediction model was screened out. A prospective cohort study enrolling 638 HHcy patients was performed. We used a logistic regression model to estimate the associations of two GRS methods with the efficacy. Performances were compared using area under the receiver operating characteristic curve (AUC). The simple count genetic risk score (SC-GRS) and weighted genetic risk score (wGRS) were found to be independently associated with the efficacy of folic acid treatment for HHcy. Using the SC-GRS, per risk allele increased with a 1·46-fold increased failure risk (P < 0·001) after adjustment for traditional risk factors, including age, sex, BMI, smoking, alcohol consumption, history of diabetes, history of hypertension, history of hyperlipidaemia, history of stroke and history of CHD. When used the wGRS, the association was strengthened (OR = 2·08, P < 0·001). Addition of the SC-GRS and wGRS to the traditional risk model significantly improved the predictive ability by AUC (0·859). A precise gene-environment predictive model with good performance was developed for predicting the treatment failure rate of folic acid therapy for HHcy.

Wet-chemical synthesized MCMB@Si@C microspheres for high-performance lithium-ion battery anodes.

MCMB@Si@C microspheres, in which silicon nanoparticles were closely connected with mesocarbon microbeads (MCMBs) through strong chemical bonds, were synthesized as high-performance Li-ion battery anodes for the first time. Furthermore, the different surface functional groups, as interconnecting species, and their effects on the anode performance were characterized in detail.