Risk factors for ≥high-grade anal intraepithelial lesions in MSM living with HIV and the response to topical and surgical treatments

The authors are grateful to MercedesA ´ lvarez Romero for coordinating patients and drawing blood samples and to Marina Gutie´rrez and Rodrigo Lo´pez of the Pathology Department for processing samples. The authors are grateful to the participating patients.Background The objective of this study in MSM living with HIV was to determine the incidence of HSIL and ASCC, related factors, and the response to treatment. Patients and methods Data were gathered in 405 consecutive HIV-infected MSM (May 2010-December 2018) at baseline and annually on: sexual behavior, anal cytology, and HPV PCR and/or high-resolution anoscopy results. They could choose mucosectomy with electric scalpel (from May 2010) or self-administration of 5% imiquimod 3 times weekly for 16 weeks (from November 2013). A multivariate logistic regression model was developed for ≥HSIL-related factors using a step-wise approach to select variables, with a significance level of 0.05 for entry and 0.10 for exit, applying the Hosmer-Lemeshow test to assess the goodness of fit. Results The study included 405 patients with a mean age of 36.2 years; 56.7% had bachelor´s degree, and 52.8% were smokers. They had a mean of 1 (IQR 1–7) sexual partner in the previous 12 months, median time since HIV diagnosis of 2 years, and mean CD4 nadir of 367.9 cells/uL; 86.7% were receiving ART, the mean CD4 level was 689.6 cells/uL, mean CD4/CD8 ratio was 0.77, and 85.9% of patients were undetectable. Incidence rates were 30.86/1,000 patient-years for ≥high squamous intraepithelial lesion (HSIL) and 81.22/100,000 for anal squamous cell carcinoma (ASCC). The ≥HSIL incidence significantly decreased from 42.9% (9/21) in 2010 to 4.1% (10/254) in 2018 (p = 0.034). ≥HSIL risk factors were infection with HPV 11 (OR 3.81; 95%CI 1.76–8.24), HPV 16 (OR 2.69, 95%CI 1.22–5.99), HPV 18 (OR 2.73, 95%CI 1.01–7.36), HPV 53 (OR 2.97, 95%CI 1.002–8.79); HPV 61 (OR 11.88, 95%CI 3.67–38.53); HPV 68 (OR 2.44, CI 95% 1.03–5.8); low CD4 nadir (OR1.002; 95%CI 1–1.004) and history of AIDS (OR 2.373, CI 95% 1.009–5.577). Among HSIL-positive patients, the response rate was higher after imiquimod than after surgical excision (96.7% vs 73.3%, p = 0.009) and there were fewer re-treatments (2.7% vs 23.4%, p = 0.02) and adverse events (2.7% vs 100%, p = 0.046); none developed ASCC. Conclusions HSIL screening and treatment programs reduce the incidence of HSIL, which is related to chronic HPV infection and poor immunological status. Self-administration of 5% imiquimod as first-line treatment of HSIL is more effective than surgery in HIV+ MSM

ART is key to clearing oncogenic HPV genotypes (HR-HPV) in anal mucosa of HIV-positive MSM

Background: Anal squamous cell carcinoma (ASCC) is one of the most frequent non-AIDS-defining neoplasias in HIV patients, mainly in MSM, and it has been associated with chronic infection with high-risk human papilloma virus (HR-HPV). Our main objective was to determine HR-HPV clearance and acquisition rates and related factors and their relationship with the incidence of HSILs and ASCC in anal mucosa of HIV+ MSM. Patients and methods: The study included consecutive HIV-infected MSM between May 2010 and December 2018. Data were gathered at baseline and annually on their sexual behavior, CD4 and CD8 levels, plasma HIV viral load, and results of anal cytology, HPV PCR, and high-resolution anoscopy. Results: Out of the 405 patients studied, 34.9% of patients cleared oncogenic genotypes (IQR: 37-69) within 49 months, and 42.9% acquired new genotypes within 36 months (IQR:12-60). In multivariate analysis, clearance was only significantly influenced by the duration of antiretroviral therapy (ART) (OR: 1.016, 95% CI 1.003-1.030). The incidence of HSILs was 30.86/1,000 patient-years and that of ASCC was 81.22/100,000 patient-years; these incidences were not influenced by the acquisition (acquired: 14.9% vs. non-acquired: 10.4%; p = 0.238) or clearance (cleared 11.4% vs. non-cleared: 13.2%; p = 0.662) rates of these viruses. Conclusions: The duration of ART appears to positively affect oncogenic genotype clearance in the anal mucosa of HIV+ MSM, although this clearance does not affect the incidence of HSILs or ASCC. The reduction in HSIL+ rate observed in our patients may be attributable to the bundle of measures adopted at our center

Association between Birth Plan Use and Maternal and Neonatal Outcomes in Southern Spain: A Case-Control Study

Background: Birth plans are used for pregnant women to express their wishes and expectations about childbirth. The aim of this study was to compare obstetric and neonatal outcomes between women with and without birth plans. Methods: A multicentre, retrospective case–control study at tertiary hospitals in southern Spain between 2009 and 2013 was conducted. A total of 457 pregnant women were included, 178 with and 279 without birth plans. Women with low-risk gestation, at full-term and having been in labour were included. Sociodemographic, obstetric and neonatal variables were analysed and comparisons were established. Results: Women with birth plans were older, more educated and more commonly primiparous. Caesarean sections were less common in primiparous women with birth plans (18% vs. 29%, p = 0.027); however, no significant differences were found in instrumented births, 3rd–4th-degree tears or episiotomy rates. Newborns of primiparous women with birth plans obtained better results on 1 min Apgar scores, umbilical cord pH and advanced neonatal resuscitation. No significant differences were found on 5 min Apgar scores or other variables for multiparous women. Conclusions: Birth plans were related to less intervention, a more natural process of birth and better outcomes for mothers and newborns. Birth plans can improve the welfare of the mother and newborn, leading to birth in a more natural way

Ontogenetic Responses of Calanus chilensis to Hypoxia from Northern Chile (23ºS), Humboldt Current Ecosystem

Eastern Boundary Upwelling Systems are being subjected to expansion, intensification and shoaling of Oxygen Minimum Zones (OMZ's), as a result of ongoing climate change. To understand how dominant epipelagic copepods may respond to stressful conditions induced by low oxygen, we experimentally studied the effect of hypoxia over the stage-specific physiology of Calanus chilensis from the Mejillones Bay (23°S — 70°W), northern Chile, during the winters of 2013 and 2014. Females, eggs and nauplii (NI to NIV) of C. chilensis were incubated under hypoxia (~0.7 mg O2 L-1) and normoxia (~8.3 mg O2 L-1) conditions at a constant temperature of 14ºC as to estimate egg production rate (EPR), hatching success (HS) and naupliar growth and development time. Additionally, we estimated survivorship by using Neutral Red technique, and also examined female metabolism by measuring specific activity of the enzymes Aminoacyl-tRNA synthetases (spAARS) (growth index) and the electron transport system (spETS) (potential respiration). Survival of females and EPR were not significantly affected by dissolved oxygen (DO) conditions, coinciding with no significant changes in their metabolism. By contrast, HS was reduced from normoxia (70%) to hypoxia (30%), whereas naupliar growth (NI to NIII) was lower under hypoxia (0.155 ± 0.007 d-1) than normoxia (0.237 ± 0.006 d-1), resulting also in a longer development time, 6.490 ± 0.353 d and 4.238 ± 0.149 d, respectively. Most eggs and nauplii collected at the end of the experiments were alive, although a higher proportion of organisms were recovered in normoxia than hypoxia. Our results revealed stage-specific responses to hypoxia in C. chilensis and the importance of ontogenetic responses to variable levels of oxygenation in the upwelling zone

Interplay between productive traits, the social rank, and the cow’s stability in the order of entrance to the milking parlour

The aim of this study was to investigate whether social rank (SR) and stability in the order of entrance to the milking parlour are associated with production traits. The study was conducted on a dairy farm where cows (n = 215) were managed in three groups according to lactation stage (group 1: 78 cows, 0–100 days in milk (DIM); group 2: 65 cows, 101–200 DIM and group 3: 72 cows, >200 DIM). SR was calculated from observations made from agonistic behaviour performed at the water troughs and feed bunks of each pen (n = 3). The animals were classified into three levels of dominance based on at least five clear interactions, resulting in: 61 dominant, 75 intermediate and 69 subordinate cows based on SR. Stability in the order of entry was estimated as the standard deviation of the entry position. SR was weakly correlated with milk yield, urea and protein content in milk. The results showed that stable cows had higher milk production and entered the milking parlour after the non-stable animals. Stability in the order of entry to the milking parlour was not affected by SR. Overall, the use of milking facilities appears to be associated with production traits rather than SR

Integration of the specialty of flamenco in the superior degree of music

A learning experience developed in a Conservatory of Music that integrates both students of classical and flamenco tradition by means of the flamenco orchestral practice is presented. The teaching sequence and a research about the self-perception of students on their learning are exemplified. 47 students completed a self-report. The results indicate that students of both traditions favorably value the aspects that are novel to them. The results of both the experience and the research are discussed in relation to the bases of collaborative and meaningful learning

Effect of monotherapy with darunavir/ cobicistat on viral load and semen quality of HIV-1 patients

Many patients previously using darunavir/ritonavir (DRV/r) (800/100mg) have switched to darunavir/cobicistat (DRV/C) (800/150 mg) either as part of triple therapy (ART) or as monotherapy with DRV (mDRV). The latter approach continues to be used in some countries for patients receiving long-term treatment. However, to date, the behaviour of DRV/C in the seminal compartment has not been analysed. This study explores how the combination behaves in monotherapy, with respect to the control of viral load and seminal quality. To this end, we studied 20 patients who were treated with mDRV/C after previous treatment with mDRV/r for at least 24 weeks. A viral load control in seminal plasma similar to that published in the literature was observed after 24 weeks of treatment with mDRV/C (viral load positivity in 20% of patients). Similarly, semen quality was confirmed (70% normozoospermic) in patients treated with this formulation, as has previously been reported for ART and mDRV/r. The DRV levels measured in seminal plasma were above EC50, regardless of whether the seminal viral load was positive or negative. We conclude that this mDRV/C co-formulation behaves like mDRV/r in seminal plasma in terms of viral load control and semen quality

Rildo: Real-World Multicenter Study on the Effectiveness and Safety of Single-Tablet Regimen of Dolutegravir plus Rilpivirine in Treatment-Experienced People Living with HIV

Two-drug regimens (2DRs) are emerging in clinical practice guidelines as treatment option for both naive and treatment-experienced people living with HIV (PLHIV). Objectives: To determine the real-life effectiveness of 2DR with 25 mg RPV plus 50 mg DTG in a single-tablet regimen (RPV/DTGSTR) and its impact on viral and immune status, lipid profile, and inflammatory markers. Methods: This observational study included 291 treatment-experienced PLHIV, starting 2DR with RPV/DTGSTR between 29 January 2019 and 2 February 2022, who were followed up for at least six months. Participants gave verbal informed consent for the switch in antiretroviral therapy (ART) to RPV/DTGSTR. Results: The mean age of the 291 participants was 51.3 years; 77.7% were male; and 42.9% were in the AIDS stage with a CD4 nadir of 283.5 ± 204.6 cells/uL. The median time since HIV diagnosis was 19.7 years (IQR: 10.6-27). Before 2DR, patients received a median of five ART lines (IQR: 3-7) for 22.2 years (IQR: 14-26), with 34.4% (n = 100) receiving a three-drug regimen (3DR), 31.3% (n = 91) receiving monotherapy, and 34.4% (n = 100) receiving 2DR. The median time on RPV/DTGSTR was 14 months (IQR: 9.5-21); 1.4% were lost to the follow-up. Effectiveness was 96.2% by intention-to-treat (ITT) analysis, 97.5% by modified ITT, and 99.3% by per-protocol analysis. Virological failure was observed in 0.69%, blips in 3.5%, and switch to another ART in 1.4%. The mean lipid profile improved, with reductions in TC/HDLc ratio (3.9 ± 0.9 vs. 3.6 ± 0.9; p = 0.0001), LDLc (118.3 ± 32.2 mg/dL vs. 106.2 ± 29.8 mg/dL, p = 0.0001), TG (130.9 ± 73.9 mg/dL vs. 115.9 ± 68.5 mg/dL, p = 0.0001), and CD4/CD8 ratio increase (0.99 ± 0.58 vs. 1.01 ± 0.54; p = 0.0001). The cost-effectiveness of 2DR with RPV/DTGSTR was similar to that of DTG/3TC and superior to those of BIC/TAF/FTC and DRV/c/TAF/FTC, with higher virological suppression and lower annual costs. Conclusions: The switch to RPV plus DTG in STR is a cost-effective, long-lasting, and robust strategy for PLHIV, with a very long experience of treatment, which improves the lipid profile without affecting inflammatory markers

Prevalence and Mode of Birth in Late Fetal Mortality in Spain, 2016–2019

Background: The rate of cesarean sections in late fetal mortality remains high. We aimed to determine the prevalence of late fetal mortality in Spain and risk factors for cesarean birth in women with stillbirth ≥ 28 weeks gestation between 2016–2019. (2) Methods: A retrospective observational study with national data between 2016–2019. A total of 3504 births with fetal dead were included. Sociodemographic, obstetrical and neonatal variables were analyzed using univariate and multivariate logistic regression (MLR), with cesarean birth with a stillborn ≥ 28 weeks gestation as the dependent variable. (3) Results: The late fetal mortality rate was 2.8 × 1000; 22.7% of births were by cesarean section. Factors associated with cesarean were having a multiple birth (aOR 6.78); stillbirth weight (aOR 2.41); birth taking place in towns with over 50,000 inhabitants (aOR 1.34); and mother’s age ≥ 35 (aOR 1.23). (4) Conclusions: The late fetal mortality rate increased during the period. The performance of cesarean sections was associated with the mother’s age, obstetric factors and place of birth. Our findings encourage reflection on how to best put into practice national clinical and socio-educational prevention strategies, as well as the approved protocols on how childbirth should be correctly conducted

Genetic diversity of HIV in seminal plasma remains higher than in blood after short-term antiretroviral therapy

Objective: To provide insight on viral kinetics and genetic diversity of HIV in seminal plasma at baseline and 1 month after initiating antiretroviral therapy (ART). Patients and methods: Blood and seminal samples from patients with newly diagnosed HIV were obtained before ART initiation (T0) and 1 month after ART initiation (T1). HIV env genetic diversity was studied using deep sequencing Nextera and V3 chemistry in a MiSeq Illumina platform. The number of viral quasispecies (5% cut-off) and Shannon Index were used to analyse diversity. Results: Forty-seven ART-naive patients were recruited between September 2016 and November 2018. At enrolment, the number of quasispecies in blood (median 4 (IQR 2-5)) was lower than in the seminal compartment (median 6, (IQR 4-8)) (p<0.01); the Shannon Index was also higher (p<0.001) in the seminal compartment than in blood (1.77 vs 0.64). At T1, for the 13 patients with detectable HIV in both blood/seminal plasma, viral diversity remained higher (p=0.139) in seminal plasma (median 2 (IQR 1-4.5)) than in blood (median 1 (IQR 1-1.5)) Integrase inhibitors (INI)-based regimens achieved higher levels of undetectability and led more frequently to lower variability (p<0.001) than protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). Conclusion: We provide here further evidence of a larger genetic diversity in seminal plasma, both at diagnosis and short term after ART initiation. Our results strengthen previous findings on HIV diversity in seminal plasma. In addition, INIs decrease variability more rapidly than PI and NNRTI in both blood and seminal plasm