bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiviral drug resistance in Cuban children infected with HIV‐1
Authors: Pérez L , Alemán Y , Correa C , Aragonés C , González I , Pérez J , Alvarez A , Pérez L , Kourí V , Vandamme A , Van Laethem K
Published: November 2012

Between 1986 and 2011, 100 children have been diagnosed with HIV‐1 in Cuba. 38 have acquired HIV‐1 by vertical transmission, 6 by blood transfusion and 56 by sexual contacts (teenager). Currently, AZT/D4T + 3TC + NVP/KALETRA are available for the treatment of pediatric patients. The aim of the study was to monitor the subtype distribution and emergence of drug resistance in pediatric HIV‐1 infections. Plasma from 46 HIV‐1‐infected children were collected from November 2005 to November 2011, subsequently extracted, amplified and sequenced. Phylogenetic analysis was performed using Mega 4 (Neighbour joining, Kimura 2). The CPR tool v6.0 (WHO list 2009) was used to interpret transmitted drug resistance (TDR). In addition, acquired drug resistance was interpreted according to HIVdb v6.1.1. Experiments were successful for 28 samples from 20 patients (5 patients with multiple samples). At the moment of analysis, 17 children were receiving ART. The median age at diagnosis was 1.9 years, whereas the median age at sampling was 4.5 years. Ten children were male (50%), 16 (80%) were infected by vertical transmission, 1 by blood transfusion (5%) and 3 by sexual route (15%). The subtypes were CRF18_cpx (25%), CRF19_cpx (25%), B (20%), CRF20_BG (10%), G (10%), CRF24_BG (5%) and C (5%). 82.3% of the children who were receiving ART at sampling (14/17) displayed at least one drug resistance mutation. The most common NRTI and NNRT mutations were: M184V (55.5%), T215FY (16.6%) and K70R (16.6%); and K103NS (61.1%) and G190A (22.0%). In contrast, only one PI mutation, L90M (5.5%), was observed. 5.8% of these children displayed single NRTI class resistance, 17.4% single NNRTI class resistance, 59% double NRTI + NNRTI class resistance and 5.8% triple NRTI + NNRTI + PI class resistance. According to HIVdb, NRTI, NNRTI and PI resistance was present in respectively 42.8%, 58.7% and 8.08% of the treated children. High‐level NVP and EFV resistance was observed in 76.5% and 58.8%, respectively. 35.2% displayed already low‐level resistance to ETR/RPV. For NRTI, high‐level resistance to 3TC/FTC was detected in 50%. High‐level resistance to NFV was detected in only one sample. No NNRTI TDR was observed, while one patient displayed PI TDR (L90M) and another NRTI TDR (D67N, T215S and K219Q) (2/11) (18.1%). At this moment, insufficient data is available whether resistance is associated with TDR, poor adherence to treatment or poor efficacy of ART regimens in use. The present study reinforces the usefulness of resistance tests for the correct management of ART.
Is there a relationship between HIV tropism and historical genotypic resistance in treatment‐experienced patients?
Authors: Zaccarelli M , Sterrantino G , Francisci D , Di Biagio A , Di Giambenedetto S , De Luca A , Punzi G , Bruzzone B , Meini G , Zazzi M ,   ARCA Database Study Group
Published: November 2012

Purpose of the study

Since X4/DM HIV‐1 tropism is associated with poorer prognosis and worse response to treatment, the aim of this study was to assess whether X4/DM HIV‐1 tropism is also related with a higher accumulation of resistance in patients experiencing treatment failure.

Methods

HIV protease (PR) and reverse transcriptase (RT) resistance mutations and tropism test results were extracted from a national database. Viral tropism data included enhanced sensitivity Trofile assay (ESTA) and geno2pheno results at 10% false positive rate. Historical resistance mutations (HRM) for PI, NRTI and NNRTI, detected in all genotypic tests performed during patient treatment history, were selected according to IAS‐USA indications.

Summary of results

Overall, 1280 patients were included: males 65%, median age 45 years (IQR: 40–50), median CD4 nadir 116 (IQR: 34–272), median past regimens 7 (IQR: 3–12), median previous NRTI used 5 (IQR: 4–7), median previous NNRTI used 1 (IQR 1–2) and median previous PI used 3 (IQR 1–5). HIV tropism was assessed by ESTA in 271 patients (21.2%) and by geno2pheno in 1009 patients (78.8%). Four hundred and fifteen patients (32.4%) carried X4/DM virus and 321 (25.1%) had ≥1 HRM for each antiretroviral class. The mean number of HRM was higher in patients harboring X4/DM virus than in patients harboring R5 virus (5.1±6.4 vs. 4.3±5.9, p = 0.02 at ANOVA test). X4/DM strains also harbored a higher mean number of PI‐related HRM (1.8±2.8 vs. 1.5±2.6, p = 0.003) and NNRTI‐related HRM (1.2±1.6 vs. 0.9±1.4, p = 0.001), but not of NRTI‐related HRM (2.2±2.6 vs. 2.0±2.6). At logistic regression, patients with HRM for all the 3 classes had a significant higher risk of also harboring X4/DM virus (OR: 1.6, 95% CI: 1.0–2.4, p = 0.04). Moreover, X4/DM virus was found to be associated with previous use of NNRTI‐containing regimens (OR: 1.4, 95% CI: 1.1–1–9, p = 0.03) and lower CD4 nadir (OR: 0.9, 95% CI: 0.9–1.0, p = 0.001, per 50‐CD4 increase). The analysis was adjusted by number of genotypic tests, number of treatment lines, age and HV subtype. Single mutations significantly associated with X4/DM tropism were: for PI, V32I and L76V; for NRTI: M41L, K70R, L74V and T215Y and for NNRTI: E138G and V179T.

Conclusions

Our data suggest that X4/DM tropism is associated with accumulation of resistance mutations during treatment history. X4/DM tropism is also confirmed to be a marker of a more compromised clinical and immune‐virological condition.
The incidence of complications after cesarean section in HIV‐infected women with advanced WHO stages of HIV disease
Authors: Posokhova S , Shevchenko S , Popova T
Published: November 2012

Prevalence of HIV infection in Ukraine is 1.6% overall, with antenatal prevalence of 0.52%, the highest in Europe. According to national protocol, cesarean section has been recommended for women with viral load above 50 copies/mL to further prevent vertical transmission of HIV. The aim of our study was to compare the infectious complication rates after cesarean delivery in HIV‐infected women with advanced WHO stages of HIV disease who received HAART, and HIV‐infected women with I or II WHO stages.

Materials and methods

A retrospective analysis was performed on data derived from 150 HIV‐infected women with advanced WHO stages of HIV disease (group I) and 150 HIV‐infected women with I or II WHO stages (group II), who underwent cesarean delivery. Postoperative infectious morbidity in both groups was analyzed according to whether the cesarean section was an elective or emergent delivery. Descriptive, comparison analyses were performed.

Results

There was no significant difference between the both groups in terms of gravidity, parity, number of previous cesarean sections, estimated gestational age at time of delivery. It has been shown that HIV‐infected women from the group I have 2 times more factors for the appearance of postpartum infectious complications, such as anemia, the urinary tract infection, sexually transmitted infections. Both groups of women were statistically more likely to experience postpartum endometritis when being delivered by emergent cesarean section than by elective cesarean section (14.6% versus 4.6%, respectively in the group I and 5.3% versus 0.5%, respectively, in the group II), superficial or deep wound breakdown (22.6% versus 4.6%, respectively, in the first group and 5.3% versus 2.6%, respectively, in the second group). Septic pelvic thrombophlebitis was only in 2% of HIV‐infected women from the group I. Urinary tract infection had 25% HIV‐infected women in the both groups. Overall, the rate of postpartum infectious complications in the first group consist 28%, which was 2 times higher compared the second group.

Conclusion

According to our study, there was no significant difference in infectious postoperative morbidity in HIV‐infected women who delivered by elective cesarean section in the both groups. But HIV‐infected women with advanced WHO stages of HIV disease undergoing emergency cesarean section are at increased risk for post‐operative infectious complications.
Analysis of enfuvirtide resistance mutations prevalence among HIV‐1 variants circulating in Russia and CIS countries
Authors: Vasilyev A , Kazennova E , Bobkova M , Salamov G
Published: November 2012

Background

Enfuvirtide (ENF/Fuzeon/T‐20) was the first member of the class ‘fusion inhibitors’. This was approved for the treatment of HIV infection in the year 2003 in Europe and the USA. Fuzeon has not yet approved in Russia but in the near future his introduction expected. Resistance to ENF has been associated with mutations in the HR1 domain at codons 36–45. Mutations outside of this region and in the HR2 domain may also serve as secondary mutations. Unique and highly homogeneous HIV‐1 subtype A variant‐IDU‐A is the most prevailing in Russia and CIS countries. HIV‐1 genetic variants circulating in Russia and CIS countries and, in particular, variant IDU‐A are poorly studied on resistance mutations to enfuvirtide. The aim of this work was to study the prevalence of mutations associated to HIV fusion inhibitor enfuvirtide resistance in Russia and CIS countries.

Methods

We used 40 proviral DNA samples (12 IDU‐A sequences, 8 subtype B sequences, 6 subtype G sequences, 8 CRF03_AB recombinant sequences and 6 CRF02_AG recombinant sequences) isolated from peripheral blood mononuclear cells of HIV‐infected patients. All the samples belonged to enfuvirtide‐naïve patients. Fragments of env gene with coordinates 7754–8342 (corresponding to strain HXB2) were sequenced. Phylogenetic analysis was carried out using DNASTAR program package.

Results

Enfuvirtide resistance mutations were not found among viruses studied in Russia and CIS countries. The frequencies of natural polymorphism mutations associated with enfuvirtide hypersusceptibility were found to consist up to 35%, and the frequencies of accessory mutations N126K and E137K in the HR2 region‐up to 27.5%.

Conclusions

Enfuvirtide resistance mutations are rare in Russia and CIS countries. HIV‐1 genetic variants circulating in Russia and CIS countries should be sensitive to enfuvirtide. However, accessory mutations in HR2 the case of HR1 resistance mutations may contribute to resistance development by improving viral fitness.
Indirect treatment comparison of efficacy, safety and resistance of EVG/COBI/FTC/TDF (Quad) vs. RAL+FTC/TDF in treatment‐naïve HIV patients
Authors: DeJesus E , Felix J , Vandewalle B , Rabiais S , Silva M , Ferreira D , Almeida J , Piontkowsky D , Szwarcberg J
Published: November 2012

Purpose

To compare the efficacy, tolerability and resistance profile at week 48 of elvitegravir 150 mg/ cobicistat 150 mg/ emtricitabine 200 mg/ tenofovir DF 300 mg qd (QUAD) relative to raltegravir 400 mg bid + emtricitabine 200 mg/ tenofovir DF 300 mg qd (RAL+FTC/TDF) in treatment‐naïve, HIV‐1‐infected adults based on an indirect treatment comparison.

Methods

Using the phase 3 studies GS‐US‐236‐0102 (102) and STARTMRK, outcomes examined were viral suppression (HIV RNA <50 cps/mL), mean CD4+ cell count (cells/µL) change from baseline, discontinuation due to any reason and due to adverse events (AE) and resistance to EVG and RAL. Efavirenz/emtricitabine/tenofovir DF was used as the common comparator. A Bayesian generalized linear model framework for indirect treatment comparison was adopted to estimate relative and absolute treatment effects, using QUAD as baseline value.

Results

The odds ratio (OR) of viral suppression with QUAD relative to RAL+FTC/TDF was 0.98 (CI: 0.52; 1.86). Discontinuations due to any reason or AE were comparable. The OR of resistance with QUAD relative to RAL+FTC/TDF was 0.63 (CI: 0.09; 4.21). The estimated probability of viral suppression was 88.8% (CI: 85.3%; 91.9%) for QUAD; 88.8% (CI: 82.7%; 93.4%) for RAL+FTC/TDF. Mean CD4+ cell count change from baseline was estimated at 239.0 cells/µL (CI: 220.9; 257.1) for QUAD and 232.0 cells/µL (CI: 204.9; 259.2) for RAL+FTC/TDF. The estimated probability of discontinuation due to any reason is 10.6% (CI: 7.6%; 14.1%) for QUAD and 9.2% (CI: 4.9%; 15.4%) for RAL+FTC/TDF and due to AE 3.7% (CI: 2.0%; 6.0%) for QUAD and 2.9% (CI: 1.0%; 6.4%) for RAL+FTC/TDF. Integrase resistance is estimated at 2.0% (CI: 1.0%; 4.0%) for QUAD and 4.3% (CI: 1.0%; 16.0%) for RAL+FTC/TDF.

Conclusion

Comparable results were found between QUAD and RAL+FTC/TDF for the studied outcomes analyzed at week 48, in treatment‐naïve, HIV‐1‐infected patients.
First line etravirine use in naïve patients: real‐world data in a UK centre
Authors: Ward C , Shaw J , Ahmad S
Published: November 2012

Etravirine (ETV) is licensed in the UK for treatment‐experienced patients and existing data suggest ETV is an effective switch for patients intolerant of efavirenz (EFV). ETV has a favourable tolerability profile and therefore may be an attractive non‐nucleoside reverse transcriptase inhibitor (NNRTI) option in first line therapy. We present data of ETV use as a once‐daily first‐line treatment option in naïve patients. 26 treatment‐naïve patients commenced on ETV were identified through pharmacy records up until May 2012. Demographic data were collected with information on hepatitis B and C status, CD4, viral load (VL), liver function and lipids. Patients were followed for 6‐monthly intervals and outcomes recorded. Of the 26 patients identified 25 were male and one female. 19 identified as men who have sex with men (MSM), 4 heterosexual and 3 bisexual. 19 were white British and 3 black African. There were no hepatitis B or C co‐infections. ETV was prescribed as 400 mg once daily, co‐prescribed with Truvada in 24 (92.3%) patients, Kivexa in one patient, and tenofovir/abacavir combination in one patient. 3 (11.5%) patients discontinued ETV therapy, 2 due to erythematous rashes in the first 16 days and one after 5 months due to reports of unpalatability. 10 (38.5%) patients chose to dissolve ETV. Median CD4 count at ETV initiation was 326 and median VL was 30,000c/ml. 6 (23.1%) patients had a starting VL>100,000. 6‐month follow‐up data for 19 (73.1%) patients showed a median CD4 of 461 and 18 (94.7%) patients had a VL<40c/mL. One patient had a viral load of 53c/ml with a reduction from a baseline of>1,000,000c/ml. 12‐month data for 17 (65.4%) patients revealed a median CD4 count of 518 and all with VLs <40c/ml at a year. 18‐month follow‐up data of 11 (42.3%) patients showed a median CD4 of 587 and 9 with a VL<40c/ml. 2 patients had a detectable VL due to documented poor adherence. There was no significant change in median alanine transaminase (ALT), bilirubin, total cholesterol, high density lipoprotein or triglycerides from baseline to 6‐, 12‐ or 18‐month levels. Patient preference was towards a once‐daily treatment for ETV. The availability of 200mg tablets and the ease of dissolvability have further increased acceptability. VL suppression was excellent with 100%<40c/ml at 12 months without any virological failures or significant adverse events. This data has shown that ETV is a highly acceptable, effective and well tolerated first‐line treatment option.
Long‐term efficacy and safety of atazanavir/ritonavir treatment in a cohort of treatment‐naïve HIV patients: an interim analysis of the REMAIN study
Authors: Teófilo E , Knechten H , Antela A , Aleixo M , Santos J , Barlet M , Jimenez‐Exposito M
Published: November 2012

Purpose

Combined antiretroviral therapy has dramatically improved HIV‐infected individuals survival. Long‐term strategies are currently needed to achieve the goal of durable virologic suppression. However, long‐term available data for specific antiretrovirals (ARV) are limited. In clinical trials, boosted atazanavir (ATV/r) regimens has shown good efficacy and tolerability in ARV‐naïve patients for up to 4 years. The REMAIN study aimed to evaluate the long‐term outcomes of ATV/r regimens in ARV‐naïve patients in a real life setting.

Methods

Non‐comparative, observational study conducted in Germany, Portugal and Spain. Historical and longitudinal follow‐up data was extracted six monthly from the medical record of HIV‐infected, treatment‐naïve patients, who initiated an ATV/r‐regimen between 2008 and 2010. The primary endpoint was the proportion of patients remaining on ATV treatment over time. Secondary endpoints included virologic response (HIV‐1 RNA <50 c/mL and <500 c/mL), reasons for discontinuation and long‐term safety. The duration of treatment and time to virologic failure (VF) were analyzed using the Kaplan‐Meier method. Data from an interim analysis including patients with at least one year of follow‐up are reported here.

Results

A total of 411 patients were included in this interim analysis [median (Q1, Q3) follow‐up: 23.42 (16.25, 32.24) months]: 77% male; median age 40 years [min, max: 19, 78]; 16% IDUs; 18% CDC C; 18% hepatitis C. TDF/FTC was the most common backbone (85%). At baseline, median (Q1, Q3) HIV‐RNA and CD4 cell count were 4.91 (4.34, 5.34) log10 c/mL and 256 (139, 353) cells/mm3, respectively. The probability of remaining on treatment was 0.84 (95% CI: 0.80, 0.87) and 0.72 (95% CI: 0.67, 0.76) for the first and second year, respectively. After 2 years of follow‐up, 84% (95% CI: 0.79, 0.88) of patients were virologically suppressed (<50 c/mL). No major protease inhibitors mutations were observed at VF. Overall, 125 patients (30%) discontinued ATV therapy [median (Q1, Q3) time to discontinuation: 11.14 (6.24, 19.35) months]. Adverse events (AEs) were the main reason for discontinuation (n = 47, 11%). Hyperbilirubinaemia was the most common AE leading to discontinuation (14 patients). No unexpected AEs were reported.

Conclusions

In a real life clinical setting, ATV/r regimens showed durable virologic efficacy with good tolerability in an ARV‐naïve population. Data from longer follow‐up will provide additional valuable information.
Rilpivirine efficacy, virology and safety in ARV treatment‐naïve patients with viral load≤100,000 HIV‐1 RNA c/mL: ECHO and THRIVE 96‐week results
Authors: Molina J‐M , Clumeck N , Orkin C , Rimsky L , Vanveggel S , Stevens M
Published: November 2012

Background

In the ECHO and THRIVE Phase III, randomised, double‐blind trials, rilpivirine (RPV, TMC278, EDURANT) 25 mg qd showed non‐inferiority compared to efavirenz (EFV) 600 mg qd in antiretroviral (ARV) treatment‐naïve, HIV‐1‐infected adults at Weeks 48 and 96. In Europe, RPV combined with other ARVs is approved for the treatment of ARV‐naïve adults with a viral load (VL) ≤100,000 c/mL. We present results from a pooled analysis of Week 96 data from this patient subgroup.

Methods

Patients received RPV 25 mg qd or EFV 600 mg qd, both with TDF/FTC (ECHO) or TDF/FTC, AZT/3TC or ABC/3TC (THRIVE). Response rate (% VL <50 c/mL, intent‐to‐treat‐time‐to‐loss‐of‐virologic response [ITT‐TLOVR]), virologic failure in the resistance analysis (VFres) and resistance development, as well as safety and tolerability were evaluated.

Results

Baseline characteristics were similar between the 368 RPV and 329 EFV patients with baseline VL ≤100,000 c/mL. At Week 96, response rates (RPV 84% vs EFV 80%; difference 4.0% [95% CI: −1.7%, 9.7%]) and VFres percentages (8% vs 6%, respectively; p=0.46) (Table) were similar in each treatment group. A comparable proportion of VFres developed NNRTI resistance‐associated mutations (RAMs) in each group. More RPV than EFV VFres developed N(t)RTI RAMs (p=0.02). The increase in mean (95% CI) CD4+ cell count from baseline to Week 96 was 224 (208; 240) cells/mm3 for RPV and 206 (188; 225) cells/mm3 for EFV. Treatment‐related grade 2–4 overall AEs, any rash, and neurologic AEs, including dizziness were less frequent for RPV than EFV (all p<0.0001, Fisher's Exact test) (Table).

RPV N=368
EFV N=329

All
Up to Week 48
Weeks 48–96
All
Up to Week 48
Weeks 48–96

Resistance at time of failure

VFres, n (%)
28 (7.6)
20 (5.4)
7 (1.9)
20 (6.1)
14 (4.3)
6 (1.8)

VFres with genotypic data
N’=27
N’=19
N’=7
N’=17
N’=11
N’=6

developing NNRTI RAMs, n
10
7
2
6
5
1

developing N(t)RTI RAMs, n
12
8
3
2
2
0

Safety

AEs leading to discontinuation, n (%)
18 (4.9)
13 (3.5)
3 (0.8)
22 (6.7)
18 (5.5)
2 (0.6)

Grade 2–4 AEs at least possibility related to treatment,  n (%)
66 (17.9)
56 (15.2)
5 (1.4)
104 (32)
97 (29.5)
12 (3.6)

AEs of interest at least possibly related to treatment, n (%)

Any neurological AE
70 (19.0)
67 (18.2)
1 (0.3)
135 (41.0)
132 (40.1)
2 (0.6)

Dizziness
35 (9.5)
35 (9.5)
0
97 (29.5)
97 (29.5)
1 (0.3)

Any psychiatric AE
61 (16.6)
54 (14.7)
2 (0.5)
75 (22.8)
68 (20.7)
5 (1.5)

Abnormal dreams/nightmares
27 (7.3)
25 (6.8)
0
38 (11.6)
36 (10.9)
1 (0.3)

Rash (grouped term)
9 (2.4)
8 (2.2)
1 (0.3)
43 (13.1)
43 (13.1)
0

Conclusions

At Week 96, in ARV treatment‐naïve adults with baseline VL ≤100,000 c/mL, RPV demonstrated sustained antiviral efficacy similar to EFV. There were similar frequencies of RPV and EFV VFres, and RPV had a more favourable safety/tolerability profile than EFV.
Sustained virological response on second‐line antiretroviral therapy following virological failure in HIV‐infected patients in rural South Africa
Authors: Schoffelen A , Wensing A , Tempelman H , Geelen S , Hoepelman A , Barth R
Published: November 2012

Purpose of the study

Over the last decade, a massive roll‐out of antiretroviral drugs in resource‐limited settings has taken place. In general, good virological responses on first‐line antiretroviral therapy (ART) are achieved in most HIV‐infected patients residing there. Still, a growing number of patients experience virological failure over time, resulting in an increasing need for second‐line regimens [1]. This study describes the clinical, immunological and virological efficacy of protease inhibitor (PI)‐based second‐line ART in a clinic in rural South Africa.

Methods

An observational cohort study was performed on 210 patients (including 39 children) who initiated PI‐based second‐line ART at least 12 months prior to data collection. Biannual clinical, immunological and virological monitoring was performed. Primary endpoints were adequate virological response (HIV‐RNA<400 copies/ml), full virological suppression (HIV‐RNA<50 copies/ml), virological failure (HIV‐RNA>1000 after initial virological response) and on‐going viremia (HIV‐RNA never<400 copies/ml for more than six months). Data were analyzed by an on‐treatment (OT) and intention‐to‐treat (ITT) approach.

Results

Median duration of follow‐up after switch to second‐line treatment was 21 months [IQR 14–37]. 150/210 patients (71%, ITT) were in care and on treatment at the end of follow‐up and 16/210 (8%, ITT) had died. After twelve months, an adequate virological response was seen in 106/143 patients (74%, OT), of which 86/143 (60%, OT) experienced full virological suppression and 20/143 (14%, OT) showed persisting low‐level viremia (HIV‐RNA between 50 and 400 copies/ml). Furthermore, virological responses remained stable after 24 months of second‐line ART. Virological efficacy was similar amongst adult and pediatric patients. Median increase in CD4 counts from switch until end of follow‐up was 145 cells/mm3 [IQR 1–397] in adults. As in first‐line ART, we observed a lack of correlation between virological treatment failure and WHO‐defined immunological failure in PI‐based therapy.

Conclusions

Promising virological outcomes are achieved with PI‐based, second‐line antiretroviral therapy in adult and pediatric patients in rural South Africa. Results were sustainable during the two‐year follow‐up period with a high retention rate, although persisting low‐level viremia occurred in a subset of patients. The observed viro‐immunological dissociation emphasizes the need for virological monitoring.
A randomized pilot study of tenofovir/emtricitabine (TDF/FTC) + boosted atazanavir (ATV/r) vs. raltegravir (RAL BID) + ATV/r vs. RAL BID + ATV BID
Authors: Cohen C , Green J , Olivet H , Khanlou H , Burman W , Corales R , Pierone G , DeJesus E , Vanig T , Tribble M , Sweet D , Appelbaum J , Garb J
Published: November 2012

Patients virologically suppressed on TDF/FTC + ATV/r may require alternative regimens that maintain suppression while addressing some drug‐related side effects. We explored two alternative regimens that replace RTV and/or TDF/FTC. This open‐label exploratory pilot trial enrolled 43 patients on TDF/FTC + ATV/r. Subjects were randomized to one of three arms. Arm 1 (n=15) replaced TDF/FTC with RAL 400 mg BID while continuing ATV/r. Arm 2 (n=14) made two changes: TDF/FTC was stopped and RAL BID was used instead; ritonavir was stopped and ATV 300 mg BID was used. Arm CTL (n=14) continued the baseline (BL) regimen. The week 48 final endpoint is summarized. The primary endpoint was maintaining virologic suppression (<40 c/mL); secondary endpoints compared safety measures. Overall mean age was 46, with 74% Caucasian, 21% black race and 12% female; similar characteristics noted across arms. Through week 48, all but two patients maintained virologic suppression; both virologic failures (>200 c/mL on two consecutive tests) were on arm 2; both reported adherence problems and no resistance mutations were detected. Overall CD4 counts were 534/mm3 at BL and 555/mm3 at week 48. There was a significant CD4 cell count difference favoring CTL (+52/mm3) vs. arm 2 (−14/mm3), p=0.03. No significant differences across arms were noted in lipid fractions or other lab tests. There were no clinically significant EKG changes across arms. Among AEs of interest through week 48, there were more neurologic AEs on arm 1 (n=7) and 2 (n=6) vs. CTL (n=1), and more musculoskeletal events noted on arm 2 (n=7) vs. arm 1 (n=3) and CTL (n=1). Quality of life was measured with a self‐assessment Likert scale. Scores were similar across arms despite the BID dosing in two arms. Self‐reported adherence using 3‐day recall was>95% in all three arms at both baseline and week 48. In this randomized pilot study, two of the three arms maintained virologic suppression in all subjects; there were two virologic rebounds in arm 2. No resistance mutations were detected in either, and adherence issues were noted for both subjects. We also noted that the CD4 cell change was significantly less on arm 2, and there were more neurologic and musculoskeletal AEs on arm 2 vs. CTL. In this study, the use of ATV/r with either TDF/FTC or RAL was successful over 48 weeks, but unboosted BID ATV 300 mg+BID RAL 400 mg as an alternative in virologically suppressed patients should be used with caution.
Observational epidemiological study to identify the clinical profile of naïve patients starting antiretroviral (ARV) therapy in Spain
Authors: Ocampo A , Viciana P , Hevia H , Ledesma F
Published: November 2012

Purpose of the study

To identify the proportion of patients starting ARV treatment with NNRTIs or with a PI/r and to explore and compare their clinical profile establishing different factors whereby physicians select the initial ARV treatment in a Spanish clinical setting.

Methods

An observational study was conducted in two different phases. In Phase I a cross‐sectional registration was conducted for patients who initiated ARV treatment in a 6‐month period in 65 Spanish hospitals. In Phase II clinical and social‐demographic features were collected retrospectively of patients who visited HIV clinics between August and November 2010 who had started ARV treatment containing an NNRTIs or a PI/r in Phase I.

Summary of results

In Phase I, 1,687 subjects who initiated ARV treatment were registered, of which 53% started with an NNRTI‐based regimen whereas 42% started with a PI/r‐based regimen. Two percent of the treatment initiations occurred in a clinical trial. In Phase II, 642 patients were paired consecutively and retrospectively. The group of patients was composed of predominantly male subjects (81% vs 19%). The median time between diagnosis and the start of ARV treatment was 3.6±5.3 years. At the initiation of treatment, 72% of patients had a CD4 count below 350 cells/µl. Although treatment based on NNRTIs in naïve patients is the most frequent option in Spain, the analysis of clinical profiles shows that PI/r‐based therapy is more often used than NNRTIs with statistical significance in patients with high viral load, Fig. A (≥100.000 copies/ml) (58% vs 42%; OR:1,75; 95% CI: 1,26–2,43; p<0,01), with CD4 cell counts <200 cells/µl, Fig. B (68% vs 31%; OR: 2,92; 95% CI: 1,99–4,27; p<0,01), and in patients at CDC stage C (65% vs 35%; OR: 2,05; CI: 1,27–3,31; p<0,01).

image

Conclusions

In Spain, HIV is still diagnosed late (as measured by CD4 count<350 cells/µl). Treatment based on NNRTIs are more frequently used in naïve patients, although PIs/r‐based regimens play an important role being the preferred option in patients with high viral load (≥100.000 copies/ml) and low CD4 cell count (<200 cells/µl).
Polarizability Matrix Extraction of a Bianisotropic Metamaterial from the Scattering Parameters of Normally Incident Plane Waves
Authors: Karamanos T. D. , Dimitriadis A. I. , Nikolaos V. K.
Published: November 2012

In this paper, a polarizability matrix retrieval method for bianisotropic metamaterials is presented. Assuming that scatterers can be modeled by electric and magnetic pointdipoles located at their centers, the induced dipole moments are analytically related to the normally incident fields, while the scattered fields are also analytically obtained for two individual cases of normal wave incidence. The latter can be combined with the incident fields, to express the desired polarizabilities, with regard to the measured or simulated scattering parameters. In this way, the polarizability matrix can be extracted by solving the resulting non-linear system of equations. The proposed technique is applied to two different split-ring resonator structures and reveals very good agreement with previously reported techniques.
State Cannabis and Psychedelic Legislation and Microdosing Interest in the US
Authors: Yang Kevin H. , Satybaldiyeva Nora , Allen Matthew R. , Ayers John W. , Leas Eric C.
Published: June 2024

Importance

Despite growing interest in psychedelics, there is a lack of routine population-based surveillance of psychedelic microdosing (taking “subperceptual” doses of psychedelics, approximately one-twentieth to one-fifth of a full dose, over prolonged periods). Analyzing Google search queries can provide insights into public interest and help address this gap.

Objective

To analyze trends in public interest in microdosing in the US through Google search queries and assess their association with cannabis and psychedelic legislative reforms.

Design, Setting, and Participants

In this cross-sectional study, a dynamic event-time difference-in-difference time series analysis was used to assess the impact of cannabis and psychedelic legislation on microdosing search rates from January 1, 2010, to December 31, 2023. Google search rates mentioning “microdosing,” “micro dosing,” “microdose,” or “micro dose” within the US and across US states were measured in aggregate.

Exposure

Enactment of (1) local psychedelic decriminalization laws; (2) legalization of psychedelic-assisted therapy and statewide psychedelic decriminalization; (3) statewide medical cannabis use laws; (4) statewide recreational cannabis use laws; and (5) all cannabis and psychedelic use restricted.

Main Outcome and Measures

Microdosing searches per 10 million Google queries were measured, examining annual and monthly changes in search rates across the US, including frequency and nature of related searches.

Results

Searches for microdosing in the US remained stable until 2014, then increased annually thereafter, with a cumulative increase by a factor of 13.4 from 2015 to 2023 (7.9 per 10 million to 105.6 per 10 million searches, respectively). In 2023, there were 3.0 million microdosing searches in the US. Analysis at the state level revealed that local psychedelic decriminalization laws were associated with an increase in search rates by 22.4 per 10 million (95% CI, 7.5-37.2), statewide psychedelic therapeutic legalization and decriminalization were associated with an increase in search rates by 28.9 per 10 million (95% CI, 16.5-41.2), statewide recreational cannabis laws were associated with an increase in search rates by 40.9 per 10 million (95% CI, 28.6-53.3), and statewide medical cannabis laws were associated with an increase in search rates by 11.5 per 10 million (95% CI, 6.0-16.9). From August through December 2023, 27.0% of the variation in monthly microdosing search rates between states was explained by differences in cannabis and psychedelics legal status.

Conclusion and Relevance

This cross-sectional study found that state-led legislative reforms on cannabis and psychedelics were associated with increased public interest in microdosing psychedelics.
Semirecumbent Positioning During Anesthesia Recovery and Postoperative Hypoxemia
Authors: Wang Xinghe , Guo Kedi , Sun Jia , Yang Yuping , Wu Yan , Tang Xihui , Xu Yuqing , Chen Qingsong , Zeng Si , Wang Liwei , Liu Su
Published: June 2024

Importance

The efficacy of a semirecumbent position (SRP) in reducing postoperative hypoxemia during anesthesia emergence is unclear despite its widespread use.

Objective

To determine the differences in postoperative hypoxemia between patients in an SRP and a supine position.

Design, Setting, and Participants

This randomized clinical trial was performed at a tertiary hospital in China between March 20, 2021, and May 10, 2022. Patients scheduled to undergo laparoscopic upper abdominal surgery under general anesthesia were enrolled. Study recruitment and follow-up are complete.

Interventions

Patients were randomized to 1 of the following positions at the end of the operation until leaving the postanesthesia care unit: supine (group S), 15° SRP (group F), or 30° SRP (group T).

Main Outcomes and Measures

The primary outcome was the incidence of postoperative hypoxemia in the postanesthesia care unit. Severe hypoxemia was also evaluated.

Results

Out of 700 patients (364 men [52.0%]; mean [SD] age, 47.8 [11.3] years), 233 were randomized to group S (126 men [54.1%]; mean [SD] age, 48.2 [10.9] years), 233 to group F (122 men [52.4%]; mean [SD] age, 48.1 [10.9] years), and 234 to group T (118 women [50.4%]; mean [SD] age, 47.2 [12.1] years). Postoperative hypoxemia differed significantly among the 3 groups (group S, 109 of 233 [46.8%]; group F, 105 of 233 [45.1%]; group T, 76 of 234 [32.5%]; P = .002). This difference was statistically significant for groups T vs S (risk ratio [RR], 0.69 [95% CI, 0.55-0.87]; P = .002) and groups T vs F (RR, 0.72 [95% CI, 0.57-0.91]; P = .007), but not for groups F vs S (RR, 0.96 [95% CI, 0.79-1.17]; P = .78). Severe hypoxemia also differed among the 3 groups (group S, 61 of 233 [26.2%]; group F, 53 of 233 [22.7%]; group T, 36 of 234 [15.4%]; P = .01). This difference was statistically significant for groups T vs S (RR, 0.59 [95% CI, 0.41-0.85]; P = .005).

Conclusions and Relevance

In this randomized clinical trial of SRP during anesthesia recovery in patients undergoing laparoscopic upper abdominal surgery, postoperative hypoxemia was significantly reduced in group T compared with group F or group S.

Trial Registration

Chinese Clinical Trial Registry Identifier: ChiCTR2100045087
Heat Exposure and Dementia-Related Mortality in China
Authors: Gao Ya , Lin Lin , Yin Peng , Kan Haidong , Chen Renjie , Zhou Maigeng
Published: June 2024

Importance

Although existing research has found daily heat to be associated with dementia-related outcomes, there is still a gap in understanding the differing associations of nighttime and daytime heat with dementia-related deaths.

Objectives

To quantitatively assess the risk and burden of dementia-related deaths associated with short-term nighttime and daytime heat exposure and identify potential effect modifications.

Design, Setting, and Participants

This case-crossover study analyzed individual death records for dementia across all mainland China counties from January 1, 2013, to December 31, 2019, using a time-stratified case-crossover approach. Statistical analysis was conducted from January 1, 2013, to December 31, 2019.

Exposures

Two novel heat metrics: hot night excess (HNE) and hot day excess (HDE), representing nighttime and daytime heat intensity, respectively.

Main Outcomes and Measures

Main outcomes were the relative risk and burden of dementia-related deaths associated with HNE and HDE under different definitions. Analysis was conducted with conditional logistic regression integrated with the distributed lag nonlinear model.

Results

The study involved 132 573 dementia-related deaths (mean [SD] age, 82.5 [22.5] years; 73 086 women [55.1%]). For a 95% threshold, the median hot night threshold was 24.5 °C (IQR, 20.1 °C-26.2 °C) with an HNE of 3.7 °C (IQR, 3.1 °C-4.3 °C), and the median hot day threshold was 33.3 °C (IQR, 29.9 °C-34.7 °C) with an HDE of 0.6 °C (IQR, 0.5 °C-0.8 °C). Both nighttime and daytime heat were associated with increased risk of dementia-related deaths. Hot nights’ associations with risk of dementia-related deaths persisted for 6 days, while hot days’ associations with risk of dementia-related deaths extended over 10 days. Extreme HDE had a higher relative risk of dementia-related deaths, with a greater burden associated with extreme HNE at more stringent thresholds. At a 97.5% threshold, the odds ratio for dementia-related deaths was 1.38 (95% CI, 1.22-1.55) for extreme HNE and 1.46 (95% CI, 1.27-1.68) for extreme HDE, with an attributable fraction of 1.45% (95% empirical confidence interval [95% eCI], 1.43%-1.47%) for extreme HNE and 1.10% (95% eCI, 1.08%-1.11%) for extreme HDE. Subgroup analyses suggested heightened susceptibility among females, individuals older than 75 years of age, and those with lower educational levels. Regional disparities were observed, with individuals in the south exhibiting greater sensitivity to nighttime heat and those in the north to daytime heat.

Conclusions and Relevance

Results of this nationwide case-crossover study suggest that both nighttime and daytime heat are associated with increased risk of dementia-related deaths, with a greater burden associated with nighttime heat. These findings underscore the necessity of time-specific interventions to mitigate extreme heat risk.
Kleroterion
Authors: Rhodes P. J. , Sing Robert
Published: June 2024

An Athenian device introduced in the fourth century
bce
for making allotments, for example of men to hold office or serve on juries.
Patroklos (Patroclus), Ptolemaic commander
Authors: Lanciers Eddy
Published: June 2024

Patroklos was a general (
strategos
) in the service of the Egyptian king Ptolemy II. He is best known for his role in the Chremonideian War, when he was commander‐in‐chief of the Egyptian expeditionary force sent to Greece. His activities are not only attested in Greece, but also in several other places in the eastern Aegean.
Zeuxis
Authors: Taylor Michael J.
Published: June 2024

General and governor under the Seleucid king Antiochos III, active between 221–189
bce
.
Divorce, Greek
Authors: Harris Edward M.
Published: June 2024

In Athenian law men could divorce their wives but had to return the dowry. A woman could leave her husband but had to make a declaration before the archon. A father could also compel his daughter to leave her husband and could marry her to another husband. The relatives of a widow who inherited could be compelled by her relatives to divorce her husband and marry her nearest relative. At Gortyn men could divorce their wives, and women could leave their husbands and take their property. There were no dowries at Gortyn. In Ptolemaic Egypt a marriage was dissolved when the parties ceased to live with each other.
Approach‐avoidance tendencies in proactive and reactive aggression
Authors: Van Bockstaele Bram
Published: June 2024

Aggressive behaviors have been related to approach/avoidance tendencies. In our current study, we investigated whether approach/avoidance tendencies for angry versus fearful emotional expressions were differentially predictive of children's reactive and proactive aggression. A total of 116 children (58 girls, Mage = 10.90, standard deviation SDage = 0.98) completed an approach/avoidance task (AAT) and a stimulus‐response compatibility task (SRCT), both measuring the extent to which they tended to approach or avoid angry and fearful facial expressions relative to neutral facial expressions. Children also completed a self‐report scale of reactive and proactive aggression. Although none of the approach/avoidance tendency scores correlated significantly with either of the aggression scores, stronger approach tendencies for angry faces and stronger avoidance tendencies for fearful faces in the AAT predicted more reactive aggression. Similar yet nonsignificant results were found for proactive aggression, but no effects were replicated in the SRCT. Our results thus invite the conclusion that reactive aggression is characterized by a tendency to approach angry faces and a tendency to avoid fearful faces. However, the poor discrimination between both types of aggression as well as the lack of convergence between the results of our two measures of approach/avoidance tendencies indicates that further research is needed to establish the role of approach/avoidance tendencies for emotional faces as markers for childhood aggression.
A review of intercropping systems in Western Canada
Authors: Mbanyele Vengai , Enesi Rebecca Oiza , Shaw Lana , Gorim Linda Yuya
Published: June 2024

Intercropping is gaining interest from Western Canadian producers who are looking for information on how to incorporate intercrops into their production systems. This review summarizes agronomic research on intercropping from the last 40 years in Western Canada and discusses the potential challenges of integrating intercropping into existing crop rotations while identifying challenges and possible solutions. Reviewed literature indicates that several intercrop combinations have been tested in small plots involving up to four crops simultaneously grown, with over 60% comprising pulse–oilseed combinations followed by pulse–cereal combinations at ∼30%. The land equivalent ratio (LER) for pulse–oilseed and pulse–cereal averaged 1.11 and 1.13, respectively. Key agronomic factors that influenced LER in different intercrop combinations have been summarized, and the relationship of N and seeding rate with crop grain LER and partial land equivalent ratio has been assessed. While the relationship between N rate and LER was unclear in pulse–oilseed combinations such as pea (Pisum sativum L.)–canola (Brassica napus L.), LER decreased linearly with increasing N rate (p < 0.004) in pea–barley (Hordeum vulgare L.) intercrop. We highlighted that incorporating intercrops into current rotations will decrease crop rotation lengths with possible implications for disease management. There are many logistical challenges to intercropping but new technology may help producers to adapt.
Seasonal changes in body composition in children from Maya agriculturalists in central Yucatán, Mexico
Authors: Gurri Francisco D. , Ruiz‐García Wilma , Vallejo‐Nieto Mirna I. , Molina‐Rosales Dolores O.
Published: June 2024

Introduction

Development policies have aimed to substitute subsistence agriculture for cash crops or other cash generating activities to encourage local farmers to depend on store‐bought groceries available year‐round instead of seasonal subsistence crops. In this paper, we test the hypothesis that increased dependence on store bought foods has decreased seasonal changes in nutritional status and fat mass in Maya Children from Yucatan, Mexico.

Methods

Weight for age (W/A), body mass index (BMI), and tricipital Skinfold z scores in children under the age of 10 years from 14 Maya rural towns with different degrees of development were compared longitudinally between scarcity and abundance seasons using a repeated measures analysis of variance. Height for age (H/A) z scores were also estimated.

Results

Origin of food consumed corresponded to the town's degree of development. Nutritional status (W/Az) and adiposity, BMI, and tricipital z scores were significantly lower during the scarcity season in every community. W/Az, tricipital skinfold z, and H/Az scores were significantly higher in developed than in traditional towns, yet in both types of town W/Az and H/Az scores were below the WHO standard mean. Tricipital skinfold z score was only below the WHO standard amongst traditional towns during the scarcity season.

Conclusions

Increased dependence on store foods failed to eliminate significant losses in body fat during the scarcity season. This failure may be affecting linear growth and promoting a thrifty phenotype that is seen in short and stocky individuals with a tendency to accumulate fat during abundance seasons.
Role of short‐chain fatty acids in host physiology
Authors: Liu Mingyue , Lu Yubo , Xue Guoyu , Han Le , Jia Hanbing , Wang Zi , Zhang Jia , Liu Peng , Yang Chaojuan , Zhou Yingjie
Published: June 2024

Short‐chain fatty acids (SCFAs) are major metabolites produced by the gut microbiota through the fermentation of dietary fiber, and they have garnered significant attention due to their close association with host health. As important mediators between the gut microbiota and the host, SCFAs serve as energy substrates for intestinal epithelial cells and maintain homeostasis in host immune and energy metabolism by influencing host epigenetics, activating G protein‐coupled receptors, and inhibiting pathogenic microbial infections. This review provides a comprehensive summary of SCFAs synthesis and metabolism and offering an overview of the latest research progress on their roles in protecting gut health, enhancing energy metabolism, mitigating diseases such as cancer, obesity, and diabetes, modulating the gut‐brain axis and gut‐lung axis, and promoting bone health.
Direct Benzylic C−H Etherification Enabled by Base‐Promoted Halogen Transfer
Authors: Bone Kendelyn I. , Puleo Thomas R. , Delost Michael D. , Shimizu Yuka , Bandar Jeffrey S.
Published: June 2024

We disclose a benzylic C−H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence. The combination of tert‐butoxide bases with 2‐halothiophene halogen oxidants enables the first general protocol for generating and using benzyl halides through a deprotonative pathway. In contrast to existing radical‐based methods for C−H functionalization, this process is guided by C−H acidity trends. This gives rise to new synthetic capabilities, including the ability to functionalize diverse methyl(hetero)arenes, tolerance of oxidizable and nucleophilic functional groups, precision site‐selectivity for polyalkylarenes and use of a double C−H etherification process to controllably oxidize methylarenes to benzaldehydes.
Eine RNA‐Sequenz in zwei Faltungen: Ein Ribozym mit Vielseitigen Fähigkeiten zur Substratprozessierung
Authors: Zhu Jikang , Dierks Dorothea , Möller Christina , Balke Darko , Müller Sabine
Published: June 2024

Wir berichten über das Design einer RNA‐Sequenz, die zwei verschiedene Ribozym‐Faltungen annehmen und die Spaltung und/oder Ligation der jeweiligen Substrate katalysieren kann. Diese RNA ist in der Lage, ihre Konformation als Reaktion auf ihre Umgebung zu ändern, weshalb wir sie als Chamäleon‐Ribozym (CHR) bezeichnen. Die effiziente RNA‐Spaltung von zwei verschiedenen Substraten sowie die RNA‐Ligation durch CHR wurde in separaten Experimenten und in einer Ein‐Topf‐Reaktion nachgewiesen. Unsere Studie zeigt, dass sich Sequenzvarianten des Hairpin‐Ribozyms mit dem Hammerhead‐Ribozym überschneiden und dass relativ kurze RNA‐Moleküle eine große konformationelle Flexibilität aufweisen können, was ein wichtiges Kriterium für die Entstehung neuer funktioneller Faltungen in der frühen Evolution ist.