Trends in and Risk Factors for Drug Resistance in Mycobacterium tuberculosis in HIV-Infected Patients.

Trends in and risk factors for drug resistance in Mycobacterium tuberculosis (M. tuberculosis) in human immunodeficiency virus (HIV)-infected patients with active tuberculosis were analyzed. The clinical data of M. tuberculosis and HIV-coinfected patients treated at the Shanghai Public Health Clinical Center between 2010 and 2022 were collected. The diagnosis of tuberculosis was confirmed by solid or liquid culture. The phenotypic drug susceptibility test was carried out via the proportional method, and the resistance to first-line and second-line drugs was analyzed. Logistic regression analysis was performed to identify associated risk factors for drug resistance in M. tuberculosis. Of the 304 patients with a M. tuberculosis-positive culture and first-line drug susceptibility test results, 114 (37.5%) were resistant to at least one first-line anti-tuberculosis drug. Of the 93 patients with first-line and second-line drug susceptibility test results, 40 (43%) were resistant to at least one anti-tuberculosis drug, and 20 (21.5%), 27 (29.0%), 19 (20.4%), 16 (17.2%), and 14 (15.1%) were resistant to rifampicin, streptomycin, ofloxacin, levofloxacin, and moxifloxacin, respectively; 17 patients (18.3%) had multidrug-resistant tuberculosis (MDR-TB). Between 2010 and 2021, the rate of resistance to streptomycin and rifampicin ranged from 14.3% to 40.0% and from 8.0% to 26.3%, respectively, showing an increasing trend year by year. From 2016 to 2021, the rate of resistance to quinolones fluctuated between 7.7% and 27.8%, exhibiting an overall upward trend. Logistic regression analysis showed that being aged <60 years old was a risk factor for streptomycin resistance, mono-drug resistance, and any-drug resistance (RR 4.139, p = 0.023; RR 7.734, p = 0.047; RR 3.733, p = 0.009). Retreatment tuberculosis was a risk factor for resistance to rifampicin, ofloxacin, of levofloxacin (RR 2.984, p = 0.047; RR 4.517, p = 0.038; RR 6.277, p = 0.014). The drug resistance rates of M. tuberculosis to rifampicin and to quinolones in HIV/AIDS patients were high and have been increasing year by year. Age and a history of previous anti-tuberculosis treatment were the main factors associated with the development of drug resistance in HIV/AIDS patients with tuberculosis.

Antidepressant use and ovarian cancer risk: Evidence from nationwide studies with >14,000 cases from Denmark and Sweden.

OBJECTIVE: Given that the evidence regarding the link between antidepressant use and ovarian cancer risk is equivocal, we investigated this research question by conducting two nationwide nested case-control studies among the Danish and Swedish populations. METHODS: Altogether, 14,121 women with epithelial ovarian cancer (30-84 years old) (Denmark: 8976 diagnosed 2000-2019, Sweden: 5145 diagnosed 2010-2018) were randomly age-matched with 564,840 female controls (359,040 from Denmark, and 205,800 from Sweden) using risk set sampling. We used conditional logistic regression to estimate odds ratios (OR) with 95 % confidence intervals (CI) and combined the estimates based on the fixed-effect assumption. We also investigated potential effect modification by well-established risk factors for ovarian cancer. RESULTS: Antidepressant use was associated with an overall reduced risk of ovarian cancer (OR = 0.92, 95%CI: 0.88-0.96), and that reduction was more pronounced in postmenopausal women and long-term users. The effect was most pronounced for serous ovarian tumors (OR = 0.90, 95%CI: 0.86-0.95) but was also observed in other subtypes, although not statistically significant. Among different types of antidepressants, selective serotonin reuptake inhibitors in general and citalopram in particular exhibited a noteworthy reduction in ovarian cancer risk (OR = 0.89, 95%CI: 0.82-0.96). Additionally, use of oral contraceptives and hormone replacement therapy individually modified the association between antidepressant use and ovarian cancer risk. CONCLUSIONS: Use of an antidepressant was associated with a slight, but statistically significant, decrease in ovarian cancer risk. Given the morbidity and mortality associated with ovarian cancer, and increasing use of antidepressants, these findings may be of significance to cancer prevention and should be studied in more detail mechanistically.

Incidence of oncogenic HPV infection in women with and without mental illness: A population-based cohort study in Sweden.

BACKGROUND: Women with mental illness experience an increased risk of cervical cancer. The excess risk is partly due to low participation in cervical screening; however, it remains unknown whether it is also attributable to an increased risk of infection with human papillomavirus (HPV). We aimed to examine whether women with mental illness had an increased infection rate of HPV compared to women without mental illness. METHODS AND FINDINGS: Using a cohort design, we analyzed all 337,116 women aged 30 to 64 and living in Stockholm, who had a negative test result of 14 high-risk HPV subtypes in HPV-based screening, during August 2014 to December 2019. We defined women as exposed to mental illness if they had a specialist diagnosis of mental disorder or had a filled prescription of psychotropic medication. We identified incident infection of any high-risk HPV during follow-up and fitted multivariable Cox models to estimate hazard ratios (HR) with 95% confidence intervals (CI) for HPV infection. A total of 3,263 women were tested positive for high-risk HPV during follow-up (median: 2.21 years; range: 0 to 5.42 years). The absolute infection rate of HPV was higher among women with a specialist diagnosis of mental disorder (HR = 1.45; 95% CI [1.34, 1.57]; p < 0.001) or a filled prescription of psychotropic medication (HR = 1.67; 95% CI [1.55, 1.79]; p < 0.001), compared to women without such. The increment in absolute infection rate was noted for depression, anxiety, stress-related disorder, substance-related disorder, and ADHD, and for use of antidepressants, anxiolytics, sedatives, and hypnotics, and was consistent across age groups. The main limitations included selection of the female population in Stockholm as they must have at least 1 negative test result of HPV, and relatively short follow-up as HPV-based screening was only introduced in 2014 in Stockholm. CONCLUSIONS: Mental illness is associated with an increased infection rate of high-risk HPV in women. Our findings motivate refined approaches to facilitate the WHO elimination agenda of cervical cancer among these marginalized women worldwide.

Low-dose aspirin use and risk of ovarian cancer: a combined analysis from two nationwide studies in Denmark and Sweden.

BACKGROUND: Studies on association between low-dose aspirin use and ovarian cancer risk were mostly based on self-reported medication use and few had large enough sample size to investigate the potential modification effect by ovarian cancer risk factors. METHODS: In these two nationwide nested case-control studies among the Danish and Swedish female population, 11,874 women with ovarian cancer (30-84 years old) (Denmark: 7328 diagnosed in 2000-2019, Sweden: 4546 diagnosed in 2010-2018) were randomly age- matched with 473,960 female controls (293,120 from Denmark, and 181,840 from Sweden). We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) and combined the estimates based the fixed-effect assumption. Effect modification by inflammation-related risk factors and by indication (cardiovascular disease, CVD) were also investigated. RESULTS: Ever use of low-dose aspirin was not strongly associated with the overall risk of ovarian cancer (OR = 0.97; 95%CI: 0.92-1.03). However, the association differed according to parity (nulliparous: OR = 0.80, 95%CI: 0.70-0.92; parous: OR = 1.00, 95%CI: 0.94-1.07; p-interaction = 0.0024), and according to history of CVD (no CVD: OR = 0.91, 95%CI: 0.82-1.00; ever CVD: OR = 1.05, 95%CI: 0.97-1.13; p-interaction =0.0204). CONCLUSIONS: Low-dose aspirin use was associated with a decreased ovarian cancer risk especially in nulliparous women and in women without CVD diagnosis.

Role of thymosin α1 in restoring immune response in immunological nonresponders living with HIV.

BACKGROUND: Immunological nonresponders (INRs) living with HIV are at increased risk of co-infection and multiple tumors, with no effective strategy currently available to restore their T-cell immune response. This study aimed to explore the safety and efficacy of thymosin α1 in reconstituting the immune response in INRs. METHODS: INRs with CD4 + T cell counts between 100 and 350 cells/µL were enrolled and received two-staged 1.6 mg thymosin α1 subcutaneous injections for 24 weeks (daily in the first 2 weeks and biweekly in the subsequent 22 weeks) while continuing antiretroviral therapy. T cell counts and subsets, the expression of PD-1 and TIM-3 on T cells, and signal joint T cell receptor excision circles (sjTREC) at week 24 were evaluated as endpoints. RESULTS: Twenty three INRs were screened for eligibility, and 20 received treatment. The majority were male (19/20), with a median age of 48.1 years (interquartile range: 40.5-57.0) and had received antiretroviral therapy for 5.0 (3.0, 7.3) years. Multiple comparisons indicated that CD4 + T cell count and sjTREC increased after initiation of treatment, although no significant differences were observed at week 24 compared to baseline. Greatly, levels of CD4 + T cell proportion (17.2% vs. 29.1%, P < 0.001), naïve CD4 + and CD8 + T cell proportion (17.2% vs. 41.1%, P < 0.001; 13.8% vs. 26.6%, P = 0.008) significantly increased. Meanwhile, the proportion of CD4 + central memory T cells of HIV latent hosts (42.7% vs. 10.3%, P < 0.001) significantly decreased. Moreover, the expression of PD-1 on CD4 + T cells (14.1% vs. 6.5%, P < 0.001) and CD8 + T cells (8.5% vs. 4.1%, P < 0.001) decreased, but the expression of TIM-3 on T cellsremained unaltered at week 24. No severe adverse events were reported and HIV viral loads kept stable throughout the study. CONCLUSIONS: Thymosin α1 enhance CD4 + T cell count and thymic output albeit as a trend rather than an endpoint. Importantly, it improves immunosenescence and decreases immune exhaustion, warranting further investigation. TRIAL REGISTRATION: This single-arm prospective study was registered with ClinicalTrials.gov (NCT04963712) on July 15, 2021.

Ruthenium-catalysed direct C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidines with acyl/phosphoryl azides.

A ruthenium-catalysed arene ortho C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidine derivatives with acyl azides or phosphoryl azides as the nitrogen sources toward C-N bond formation was developed. This protocol could offer a novel and direct approach to access a series of amidated and phosphoramidated pyrrolo[2,3-d]pyrimidine derivatives in moderate to good yields, thereby evading the general Curtius rearrangement. The protocol features significant functional group tolerance and a single-step process, with the release of only innocuous molecular nitrogen as the byproduct.

Long-term follow-up of cervical cancer incidence after normal cytological findings.

An increase in cervical cancer incidence in Sweden from 2014 to 2015 has been attributed to an increase in false-negative cytological findings before cancer diagnoses. Years later, we performed a long-term follow-up to investigate whether the problem persisted. At each calendar year from 2016 to 2020, we identified women with prior normal cervical screening results through linkage to the Swedish National Cervical Screening Registry. We reported their incidence rates (IRs) of invasive cervical cancer in consecutive years and compared the IRs over time. For the years 2016 to 2020, there was no overall change in cervical cancer incidence after two normal cytology in the last two screening intervals. However, there was a further 62% increase among women 50 to 60 years of age with normal cytology in the past two screening intervals. The incidence rate of cervical cancer was high among nonscreened women and low among HPV-screened women with negative results, with no trends over time. Our results imply that the previously reported decrease in sensitivity of cervical cytology is persisting. Although primary cytology screening is no longer used, cytology is used in triaging among HPV-positive women. Our findings suggest that improved triaging is needed, for example, improved quality assurance and/or use of alternative triage tests.

Impact of cervical screening by human papillomavirus genotype: Population-based estimations.

BACKGROUND: Cervical screening programs use testing for human papillomavirus (HPV) genotypes. Different HPV types differ greatly in prevalence and oncogenicity. We estimated the impact of cervical screening and follow-up for each HPV type. METHODS AND FINDINGS: For each type of HPV, we calculated the number of women needed to screen (NNS) and number of women needing follow-up (NNF) to detect or prevent one cervical cancer case, using the following individual level input data (i) screening and cancer data for all women aged 25 to 80 years, resident in Sweden during 2004 to 2011 (N = 3,568,938); (ii) HPV type-specific prevalences and screening histories among women with cervical cancer in Sweden in 2002 to 2011(N = 4,254); (iii) HPV 16/18/other HPV prevalences in the population-based HPV screening program (N = 656,607); and (iv) exact HPV genotyping in a population-based cohort (n = 12,527). Historical screening attendance was associated with a 72% reduction of cervical cancer incidence caused by HPV16 (71.6%, 95% confidence interval (CI) [69.1%, 73.9%]) and a 54% reduction of cancer caused by HPV18 (53.8%, 95% CI [40.6%, 63.1%]). One case of HPV16-caused cervical cancer could be prevented for every 5,527 women attending screening (number needed to screen, NNS). Prevention of one case of HPV16-caused cervical cancer required follow-up of 147 HPV16-positive women (number needed to follow-up, NNF). The NNS and NNF were up to 40 to 500 times higher for HPV types commonly screened for with lower oncogenic potential (HPV35,39,51,56,59,66,68). For women below 30 years of age, NNS and NNF for HPV16 were 4,747 and 289, respectively, but >220,000 and >16,000 for HPV35,39,51,56,59,66,68. All estimates were either age-standarized or age-stratified. The primary limitation of our study is that NNS is dependent on the HPV prevalence that can differ between populations and over time. However, it can readily be recalculated in other settings and monitored when HPV type-specific prevalence changes. Other limitations include that in some age groups, there was little data and extrapolations had to be made. Finally, there were very few cervical cancer cases associated with certain HPV types in young age group. CONCLUSIONS: In this study, we observed that the impact of cervical cancer screening varies depending on the HPV type screened for. Estimating and monitoring the impact of screening by HPV type can facilitate the design of effective and efficient HPV-based cervical screening programs. TRIAL REGISTRATION: ClinicalTrials.gov with numbers NCT00479375, NCT01511328.

Overall and Cervical Cancer Survival in Patients With and Without Mental Disorders.

Importance: Individuals with a mental disorder experience substantial health disparity and are less likely to participate in cervical screening and human papillomavirus vaccination. Additionally, this population may benefit less from tertiary cancer prevention. Objective: To compare clinical characteristics and survival patterns between patients with cervical cancer with and without a preexisting diagnosis of a mental disorder at the time of cervical cancer diagnosis. Design, Setting, and Participants: This cohort study obtained data from Swedish population-based (Swedish Cancer Register, Swedish Cause of Death Register, Swedish Total Population Register, Swedish Patient Register, and Swedish Longitudinal Integration Database for Health Insurance and Labor Market Studies) and quality registries (Swedish Quality Register of Gynecologic Cancer and Swedish National Cervical Screening Register) on patients with cervical cancer. Patients who were included in the analysis were identified using the Swedish Cancer Register and were diagnosed with cervical cancer between 1978 and 2018. The Swedish Patient Register was used to identify patients with mental disorders using codes from the International Classification of Diseases, Eighth Revision and Ninth Revision and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Because data on clinical characteristics at the time of cancer diagnosis were available for only for part of the study population, 2 patient groups were created: those with cervical cancer diagnosed from 2002 to 2016 and all patients diagnosed with cervical cancer (1978-2018). Data analyses were carried out between March and September 2022. Exposure: Clinical diagnoses of a mental disorder, including substance abuse, psychotic disorders, depression, anxiety, stress-related disorders, attention-deficit/hyperactivity disorder, autism, and intellectual disability, prior to cervical cancer. Main Outcomes and Measures: Death due to any cause or due to cervical cancer as ascertained from the Swedish Cause of Death Register. Results: The sample included 20 177 females (mean [SD] age, 53.4 [17.7] years) diagnosed with cervical cancer from 1978 to 2018. In a subgroup of 6725 females (mean [SD] age, 52.2 [18.0] years) with cervical cancer diagnosed from 2002 to 2016, 893 (13.3%) had a preexisting diagnosis of a mental disorder. Compared with patients with no preexisting mental disorder diagnosis, those with a preexisting mental disorder had a higher risk of death due to any cause (hazard ratio [HR], 1.32; 95% CI, 1.17-1.48) and due to cervical cancer (HR, 1.23; 95% CI, 1.07-1.42). These risks were lower after adjustment for cancer characteristics at the time of cancer diagnosis (death due to any cause: HR, 1.19 [95% CI, 1.06-1.34] and death due to cervical cancer: HR, 1.12 [95% CI, 0.97-1.30]). Risk of death was higher for patients with substance abuse, psychotic disorders, or mental disorders requiring inpatient care. Among patients with cervical cancer diagnosed from 1978 to 2018, the estimated 5-year survival improved continuously during the study period regardless of preexisting diagnosis of a mental disorder status. For example, in 2018, the estimated 5-year overall survival proportion was 0.66 (95% CI, 0.60-0.71) and 0.74 (95% CI, 0.72-0.76) for patients with and without a preexisting diagnosis of a mental disorder, respectively. Conclusions and Relevance: Findings of this cohort study suggest that patients with cervical cancer and a preexisting diagnosis of a mental disorder have worse overall and cervical cancer-specific survival than patients without a preexisting mental disorder diagnosis, which may be partly attributable to cancer and sociodemographic characteristics at diagnosis. Hence, individuals with mental disorders deserve special attention in the tertiary prevention of cervical cancer.

Assessment of Human Papillomavirus Non-16/18, Type-Specific Risk for Cervical Intraepithelial Neoplasia Grade 3 or Worse Among Women With Cervical Atypical Glandular Cells.

OBJECTIVE: To evaluate the risk for cervical intraepithelial neoplasia grade 3 (CIN 3) or worse (including adenocarcinoma in situ [AIS] and invasive cervical cancer) associated with non-16/18 human papillomavirus (HPV) types (other HPV) among women with atypical glandular cells (AGC) in cervical cytology. METHODS: This population-based cohort study evaluates the risk of CIN 3 or worse associated with other HPV types. Human papillomavirus genotyping was performed on Pap tests collected in Sweden from 341 women with AGC that were positive for other HPV types from February 17, 2014, to December 31, 2018. The women were followed for histopathologic outcomes using comprehensive registry linkages until December 31, 2019. Cumulative incidence proportions of CIN 3 or worse by specific HPV type were calculated using 1-minus Kaplan-Meier function. Hazard ratios (HRs) for CIN 3 or worse were generated using multivariate Cox regression. RESULTS: Of 341 women, 134 (39.3%) had CIN 3-AIS, but there were only five (1.5%) women in the cohort with invasive cervical cancer. Human papillomavirus 45 preceded 80.0% of invasive cervical cancer cases. Among women positive for HPV33, 82.9% (95% CI 58.0-97.3%) had CIN 3 or worse during follow-up. Positivity for HPV31 conferred the highest HR for CIN 3 or worse relative to other types, both in primary cytology and primary HPV screening (HR 2.71, 95% CI 1.47-5.00 and HR 3.41, 95% CI 1.95-5.96, respectively). CONCLUSION: Among non-16/18 HPV types in AGC, HPV31 and 33 had the highest risk for CIN 3 or worse, whereas most of the women with invasive cancer were positive for HPV45. Extended HPV genotyping may be helpful for the management of AGC.

High coverage and adherence to dose intervals of the national school-based HPV vaccination program in Sweden during 2012-2019.

Background: Close monitoring of vaccination coverage is important for cervical cancer prevention efforts. The study aims to describe the HPV vaccination coverage by dose in girls eligible for HPV vaccination within Sweden's childhood immunization program and provide an estimate on dose timing compliance. Methods: Vaccination records between 2012 and March 2019 were obtained for girls born in 2000-2006 from the vaccination registers in Sweden. The mid-time population counts for the respective birth cohorts were taken as the denominator. Full-dose coverage and coverage with at least one dose of the vaccine were calculated within the two-dose and three-dose regimen, by region. Dose compliance was calculated within the two-dose regimen. Results: Vaccination coverage with at least one dose of the vaccine was >80% within birth cohorts 2001-2006. Full-dose coverage within a two-dose and three-dose regimen were 73.4% in birth cohorts 2004-2005, and 56.3% in birth cohorts 2000-2001, respectively. Little variation was observed in vaccination coverage between regions. Dose completion was 91.8%, and 72.8% in girls that initiated a two-dose and three-dose regimen, respectively. Among girls receiving a two-dose regimen, 93.0% received the second dose 6-12 months after dose one. Discussion: In conclusion, high levels of HPV vaccination coverage were observed with little variation between regions. Dose timing compliance was particularly high in the two-dose regimen. To fully benefit from the impact of HPV vaccination, it will be important to further push the vaccination coverage and reach the girls that do not or partially engage with HPV vaccination.

Puerarin-Tanshinone IIA Suppresses atherosclerosis inflammatory plaque via targeting succinate/HIF-1α/IL-1ß axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory injury is an important pathological factor for the formation of atherosclerotic plaque. It is well known that Puerarin and Tanshinone IIA (Pue-Tan) can significantly reduce interleukin-1ß (IL-1ß) levels and delay the atherosclerosis (AS) process clinically in China. Previous evidence has shown that the Succinate/HIF-1α/IL-1ß inflammatory signaling axis (Succinate axis) promotes the progression of atherosclerotic inflammatory plaques. It is not clear whether Pue-Tan inhibits inflammatory plaques by reducing the level of IL-1ß through the succinate signaling axis. AIM OF STUDY: Find out the interaction between Pue-Tan targets and the succinate axis by means of network pharmacology and bioinformatics analysis and to further confirm whether Pue-Tan can inhibit vascular inflammation and delay the formation of atherosclerotic inflammatory plaques by targeting the succinate signaling axis. MATERIALS AND METHODS: Firstly, animal experiments were conducted to verify the changing relationship between Succinate and IL-1ß under Pue-Tan intervention. Secondly, network pharmacology approach was employed to uncover the specific targets of Pue-Tan in the intervention of AS from multiple levels of components, proteins, and pathways, and at the same time, the target must be a key factor of the succinate signaling axis. Autodock vina1.5.6 was applied to molecular docking for Pue-Tan and target protein. Subsequently, cells experiment and animal experiment were performed to verify Pue-Tan inhibiting the inflammatory progression of atherosclerosis by targeting succinate signaling axis. RESULTS: Firstly, we first found that the reduction of IL-1ß was positively correlated with succinate in the serum of Pue-Tan-treated mice. Secondly, network pharmacology compared with molecular docking showed that hypoxia-induced factor-1α (HIF-1α) was the key target of Pue-Tan and the key node of succinate singling axis. Finally, in vitro study, Pue-Tan significantly reduced the factors of succinate axis just as HIF-1α siRNA; in vivo study, we confirmed a decreased expression of succinate axis and ICAM-1 in the aorta of ApoE-/- mice under Pue-Tan intervention, which was consistent with the in vitro results. CONCLUSION: This study confirmed that Pue-Tan blocked the succinate axis by targeting HIF-1α to prevent the formation of atherosclerotic inflammatory plaques and delay the pathological process of AS. Network Pharmacology, Bioinformatics of Molecular Docking, and Molecular Biology Validation can be used as a effective way to discover and verify the pharmacological mechanism of TCM.

Invasive cervical cancer, precancerous lesions, and cervical screening participation among women with mental illness in Sweden: a population-based observational study.

BACKGROUND: WHO aims to eliminate cervical cancer. Whether women with mental illness constitute a group at high-risk and require targeted prevention initiatives remains unknown. We aimed to assess whether women with severe mental illness, psychiatric or neurodevelopmental disorders, have an increased risk of invasive cervical cancer, and an increased risk of precancerous lesions and a lower degree of participation in cervical screening compared with women without severe mental illness. METHODS: In this population-based observational study, 4 112 598 women from 1973 to 2018 in Sweden were included to compare the risk of invasive cervical cancer, high-grade precancerous cervical lesions (CIN2+), and degree of participation in cervical screening (defined as the proportion of time covered by screening during a period when cervical screening is recommended) between women with and without mental illness. We focused on severe mental illness (ie, diagnosed in specialised psychiatric care) and also investigated milder mental illness (ie, use of psychotropic medications prescribed in primary care without specialist diagnosis) as secondary exposure. In two nested case-control studies, we defined the cases as women who have a diagnosis of invasive cervical cancer or CIN2+, and randomly selected individually matched controls from women who did not have these diagnoses. FINDINGS: Women with a specialist diagnosis of mental illness had a higher risk of invasive cervical cancer (hazard ratio 2·39, 95% CI 2·22-2·57) and CIN2+ (2·22, 2·18-2·26) and a 5·0% (4·8-5·2) lower cervical screening participation compared with matched controls. The risk increment of invasive cervical cancer and CIN2+ was greatest for substance misuse, whereas the screening reduction was greatest for intellectual disability and autism. In contrast, women who used prescribed psychotropic medications without specialist diagnosis had slightly higher screening participation and higher risk of CIN2+ but lower risk of invasive cervical cancer than women with neither specialist diagnosis nor medication use. INTERPRETATION: Women with severe mental illness participate less in screening and experience a higher risk of cervical neoplasia. Refined approaches are needed to better target these women in the elimination agenda of cervical cancer. FUNDING: Swedish Cancer Society.

HPV-induced host epigenetic reprogramming is lost upon progression to high-grade cervical intraepithelial neoplasia.

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC = 0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ = 0.48; P < .001) and negatively associated with epigenetic replicative age (ρ = -0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer.

Efficacy of Efavirenz-Based Regimen in Antiretroviral-Naïve Patients with HIV-1 V179D/E Mutations in Shanghai, China.

INTRODUCTION: This study aimed to evaluate the prevalence of HIV-1 mutation V179D/E and the effect of V179D/E on the virological response to first-line efavirenz-based regimens among antiretroviral treatment (ART)-naïve patients. METHODS: An ambispective cohort study was conducted. All ART-naïve patients who underwent baseline genotypic resistance testing between January 2019 and November 2021 were included in the analysis of the prevalence of the V179D/E mutation. Then, patients with identified V179D/E received the efavirenz-based regimen or the protease inhibitor (PI)/integrase strand transfer inhibitor (INSTI)-based regimen. The virological and immunological outcomes at week 48 were compared between the two groups. RESULTS: HIV-1 mutation V179D/E was identified in 252 out of 2568 ART-naïve patients, with a prevalence of 9.8% in Shanghai, China. A total of 206 participants were included in the efficacy analysis. Forty-six patients with altered ART regimens or incomplete follow-up data were excluded from the analysis. The baseline characteristics were comparable between the efavirenz group (n = 109) and the PI/INSTI group (n = 97). At week 48, a total of 96 participants (88.1%) in the efavirenz group and 92 participants (94.8%) in the PI/INSTI group had a viral load lower than 50 copies/mL (chi-square test, p = 0.086). In both groups, a lower proportion of participants achieved virological suppression among participants with a baseline viral load of at least 100,000 copies/mL compared with those with lower than 100,000 copies/mL (66.7% vs. 96.1% in the efavirenz group, p < 0.001; 87.1% vs. 98.4% in the PI/INSTI group, p = 0.039). The median increase from baseline in the CD4 count at week 48 was significantly greater in the PI/INSTI group (192 cells/µL) than in the efavirenz group (154 cells/µL) (p = 0.029). CONCLUSION: There is a high prevalence of V179D/E in ART-naïve patients with HIV-1 in Shanghai, China. The first-line efavirenz-based regimen may be not suitable for patients with HIV-1 mutation V179D/E, especially for those with a baseline viral load of at least 100,000 copies/mL. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2000034787).

The WID-EC test for the detection and risk prediction of endometrial cancer.

The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer.

DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID™-qCIN test.

BACKGROUND: Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients. RESULTS: The WID™-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case-control) and predictive setting (nested case-control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WID™-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WID™-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt-) index sample who were diagnosed with CIN3 1-4 years after sample donation. CONCLUSION: We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WID™-qCIN, a PCR-based DNAme test. The WID™-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case-control settings and future studies will assess performance and generalisability in a randomised controlled trial.

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer.

BACKGROUND: Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. METHODS: We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1-4 years and 218 remained disease-free. RESULTS: We developed the WID-CIN (Women's cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88-0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3-96.1) in all and 92.7% (85.9-99.6) and 65.6% (49.2-82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0-61.5) cases developing 1-4 years after sample donation in all ages or 56.9% (47.6-66.2) and 53.5% (43.7-63.2) in ≥30 and <30-year-old women, at a specificity of 75%. CONCLUSIONS: The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future.

Population pharmacokinetics and model-informed precision dosing of lamivudine in Chinese HIV-infected patients with mild and moderate impaired renal function.

BACKGROUND: Lamivudine is a first-line medication used for human immunodeficiency virus (HIV) treatment. To date, the population pharmacokinetics of lamivudine in Chinese HIV-infected adults have not been assessed. This study aimed to develop a population pharmacokinetic model for oral lamivudine in Chinese HIV-infected adults and to determine the optimal lamivudine dosage regimens. RESEARCH DESIGN AND METHODS: A total of 1113 samples, from 828 Chinese HIV-infected patients treated with lamivudine 300 mg every 24 hours, were pooled from two open-label, prospective clinical trials. A population pharmacokinetics analysis was performed using a nonlinear mixed-effects modeling method. A Monte Carlo simulation was conducted to optimize lamivudine dosing. RESULTS: A two-compartment model adequately described the population pharmacokinetics of lamivudine. The typical population estimate for apparent clearance was 28.3 L/h. Creatinine clearance was identified as a significant factor influencing apparent clearance. According to the Monte Carlo simulation, patients with creatinine clearance between 50 and 70 mL/min should receive lamivudine 200 mg every 24 h or 300 mg every 36 h, to achieve optimal lamivudine exposure. CONCLUSIONS: No obvious ethnic differences were observed in lamivudine pharmacokinetics between Chinese and Caucasian populations. Additionally, a model-informed dosage regimen is recommended for patients with impaired renal function.

Integrated traditional Chinese medicine intervention for delaying HIV morbidity: study protocol for a multicentre randomised controlled trial.

BACKGROUND: Acquired immune deficiency syndrome is caused by humans and is high worldwide. Active antiretroviral therapy emerged in the late 1990s and is effective against AIDS. However, despite the extensive research on AIDS, there is still no vaccine or cure. The benefits of traditional Chinese medicine (TCM) for AIDS are increasingly recognised, especially by patients with asymptomatic HIV infection. METHODS/DESIGN: The proposed trial will enrol 216 eligible patients who will be randomised into treatment and control groups. After 72 weeks of intervention, the efficacy and safety of TCM for patients with AIDS will be assessed. The variables that will be measured include clinical symptoms, TCM syndromes, viral load, immunological indicators, inflammatory factors, quality of life, patient-reported outcomes and safety assessment. DISCUSSION: The study aim to compare the effectiveness and safety of TCM for asymptomatic AIDS and explore its potential underlying mechanism. Additionally, the findings will provide a reference for the use of TCM to delay the onset and control the progression of HIV/AIDS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800018365. Registered on 13 September 2018.