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Background: Payment for care provided as part of clinical research has become less predictable as a result of managed care. Because little is known at present about how entry into cancer trials affects the cost of care for cancer patients, we conducted a matched case-control comparison of the incremental medical costs attributable to participation in cancer treatment trials.Methods: Case patients were residents of Olmsted County, MN, who entered phase II or phase III cancer treatment trials at the Mayo Clinic from 1988 through 1994. Control patients were patients who did not enter trials but who were eligible on the basis of tumor registry matching and medical record review. Sixty-one matched pairs were followed for up to 5 years after the date of trial entry for case patients or from an equivalent date for control patients. Hospital, physician, and ancillary service costs were estimated from a population-based cost database developed at the Mayo Clinic.Results: Trial enrollees incurred modestly (no more than 10%) higher costs over various follow-up periods. The mean cumulative 5-year cost in 1995 inflation-adjusted U.S. dollars among trial enrollees after adjustment for censoring was $46424 compared with $44 133 for control patients. After 1 year, trial enrollee costs were $24645 compared with $23 964 for control patients.Conclusions: This study suggests that cancer chemotherapy trials may not imply budget-breaking costs. Cancer itself is a high-cost illness. Clinical protocols may add relatively little to that cost. [ABSTRACT FROM AUTHOR]

Objective: To estimate the prevalence of the curable sexually transmitted infections (STIs) Chlamydia trachomatis , Neisseria gonorrhoeae , Mycoplasma genitalium , Trichomonas vaginalis and Treponema pallidum , to identify associated risk factors and to assess ciprofloxacin resistance in N. gonorrhoeae -positive specimens among female sex workers (FSWs) in Guinea-Bissau., Methods: For this cross-sectional study, FSWs were recruited from October 2014 to May 2019. A questionnaire on STI risk factors was completed by the study participants, and the women were asked to provide a vaginal swab for nucleic acid amplification tests for C. trachomatis , N. gonorrhoeae , M. genitalium , T. vaginalis (Aptima, Hologica), as well as a blood sample for T. pallidum serological testing and discriminatory HIV-testing. The prevalence of STIs was determined, and multivariate logistic regression was used to identify STI risk factors., Results: The study included 467 women. The prevalence of current infection with any curable STI was 46.7%, and the most common pathogen was T. vaginalis (26.3%), followed by M. genitalium (21.9%), C. trachomatis (11.8%), N. gonorrhoeae (10.1%) and T. pallidum (2.8%). The proportion of asymptomatic infections among the diagnosed STIs was 61.8%, 61.5%, 55.3%, 55.3% and 52.2% for C. trachomatis, T. pallidum, N. gonorrhoeae, T. vaginalis and M. genitalium, respectively . The prevalence of the gyrA S91F mutation conferring ciprofloxacin resistance in N. gonorrhoeae -positive specimens was 84.0%. Significant risk factors for having a curable STI were age and HIV-1 infection, while use of female condoms was a protective factor., Conclusion: This study demonstrated that the prevalence of curable STIs was high among FSWs in Guinea-Bissau during the study period, indicating an unmet need for STI services. Moreover, the results indicated that symptomatic treatment might be insufficient, highlighting a need for periodic aetiological testing to facilitate detection of asymptomatic as well as symptomatic STIs to stop ongoing transmission., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recurrent pregnancy loss is characterized by three or more consecutive pregnancy losses. Although the causes of recurrent pregnancy loss are often unknown, chromosomal defects and fetal anomalies account for a significant proportion of cases. Previous research has primarily focused on maternal factors, but recent attention has shifted to the role of male lifestyle factors., Objectives: This study examined how male lifestyle factors and chronic illnesses affect recurrent pregnancy loss in a Danish cohort. Objectives included analyzing demographic and clinical features, as well as assessing lifestyle factors and pregnancy outcomes., Materials and Methods: We included 741 males referred to the Danish recurrent pregnancy loss unit between 2009 and 2021, alongside a control group of 1173 males from the PREGCO study. Data on demography, clinical features, lifestyle factors, and pregnancy outcomes were collected and analyzed., Results: The recurrent pregnancy loss group had a higher mean age compared to the controls. Although there was a trend suggesting a higher prevalence of obesity in the recurrent pregnancy loss group, statistical significance was not reached. The prevalence of chronic illnesses was similar in both groups. In the recurrent pregnancy loss group, a higher body mass index and history of previous or current smoking were associated with a lower pregnancy rate, and men who never smoked had an increased likelihood of achieving pregnancy. However, these associations lost significance after adjusting for potential confounders., Discussion: The study suggests an association between male obesity and smoking, and decreased pregnancy rates after referral for recurrent pregnancy loss. However, further research is needed to understand the underlying mechanisms and establish causality in this association., Conclusion: The study reveals potential associations between male smoking, male obesity, and reduced pregnancy rates in individuals referred for recurrent pregnancy loss. These findings emphasize the importance of considering male lifestyle factors in the evaluation and management of recurrent pregnancy loss., (© 2024 American Society of Andrology and European Academy of Andrology.)

Per- and polyfluoroalkyl substances (PFAS) are a group of thousands of highly persistent anthropogenic chemicals widely used in many industries. Therefore, they are, ubiquitously present in various types of environments. Despite their omnipresence, ecotoxicological studies of most PFAS are scarce, and those available often assess the effects of long chain PFAS. In this study, we present the results of an exposure experiment in which wild aquatic amphipod Gammarus spp. was exposed to the short chain perfluorinated substance perfluorobutanoic acid (PFBA) at very low and environmentally relevant concentrations of 0, 10 and 100 ng/L. The exposure lasted for 12 days, and food intake and non-reproductive behavior were analyzed. Exposure to 10 and 100 ng/L PFBA resulted in a lower consumption of food during exposure but no effect on behavior was found., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The immune system of neonates is immature and therefore knowledge of possible early-life protection against SARS-CoV-2 infection, such as breastfeeding, is of great importance. Few studies have investigated the presence and duration of SARS-CoV-2 antibodies in breastmilk in relation to the trimester of maternal infection during pregnancy, and none with successful participation from all three trimesters. This study has dual objectives (1) in relation to the trimester of infection to examine the frequency, concentration and duration of IgA and IgG antibodies in breastmilk and blood serum in the third and sixth month post-partum in former SARS-CoV-2-infected mothers and (2) to examine the association in pediatric emergency admission of children within the first six months of life compared to children of non-SARS-CoV-2-infected women. The first objective is based on a prospective cohort and the second is based on a nested case-control design. The study participants are women with a former SARS-CoV-2 infection during pregnancy, whose serology IgG tests at delivery were still positive. Maternal blood and breastmilk samples were collected at three and six months postpartum. Serum IgA frequency three months pp was 72.7% (50%, 90% and 60% in the first, second and third trimester) and 82% six months pp (67%, 91% and 82% in the first, second and third trimester). Breastmilk IgA frequency three months pp was 27% (16.6%, 36% and 20% in first, second and third trimester) and 28% six months pp (0%, 38% and 28% in the first, second and third trimester). The highest IgA concentration in breastmilk was found six months post-partum with infection in the third trimester. Serum IgA was detectable more than 400 days post infection, and serum IgG above threshold was found 430 days after date of infection. We found no correlation between serum IgA and breastmilk IgA, nor between serum IgG and breastmilk IgA regardless of the trimester of infection.

Despite low or undetectable plasma viral load, people living with HIV-2 (PLWH2) typically progress toward AIDS. The driving forces behind HIV-2 disease progression and the role of viremia are still not known, but low-level replication in tissues is believed to play a role. To investigate the impact of viremic and aviremic HIV-2 infection on target and bystander cell pathology, we used data-independent acquisition mass spectrometry to determine plasma signatures of tissue and cell type engagement. Proteins derived from target and bystander cells in multiple tissues, such as the gastrointestinal tract and brain, were detected at elevated levels in plasma of PLWH2, compared with HIV negative controls. Moreover, viremic HIV-2 infection appeared to induce enhanced release of proteins from a broader range of tissues compared to aviremic HIV-2 infection. This study expands the knowledge on the link between plasma proteome remodeling and the pathological cell engagement in tissues during HIV-2 infection., Competing Interests: The authors or their institutions declare no competing financial interests and did not at any time receive payment or services from a third party (government, commercial, private foundation, etc.) for any aspect of the submitted work (including data monitoring board, study design, manuscript preparation, statistical analysis, etc.). The authors have no patents, whether planned, pending, or issued, broadly relevant to the work., (© 2024 The Authors.)

A palladium(0)-catalyzed aminocarbonylation reaction employing molybdenum hexacarbonyl as a carbon monoxide precursor for the production of N-capped amino acids using aryl and heteroaryl bromides and triflates is reported. The carbon monoxide is formed ex situ through the use of a two-chamber system, where carbon monoxide generated in one chamber is free to diffuse over and be consumed in the other palladium-catalyzed reaction chamber. Using this method, two series of aryl bromides and aryl triflates were utilized to synthesize 21 N-capped amino acids in isolated yields between 40 and 91%.

Intrauterine growth restriction (IUGR) is a potential complication associated with maternal SARS-CoV-2 infection. Danish guidelines recommend ultrasound follow-up from gestational age (GA) 24+0 in SARS-CoV-2-positive pregnant women who experience reduced fetal movements. This is a case report of severe IUGR (-51%) after maternal infection at GA 22+1 in a healthy unvaccinated 28-year-old woman. Positive PCR-tests for SARS-CoV-2 from placenta and child, along with massive placental inflammatory findings, suggested IUGR caused by maternal infection. This implies that follow-up from earlier GA may be warranted.

Time to AIDS in HIV-2 infection is approximately twice as long compared to in HIV-1 infection. Despite reduced viremia, HIV-2-infected individuals display signs of chronic immune activation. In HIV-1-infected individuals, B-cell hyperactivation is driven by continuous antigen exposure. However, the contribution of viremia to B-cell perturbations in HIV-2-infected individuals remains largely unexplored. Here, we used polychromatic flow cytometry, consensus hierarchical clustering and pseudotime trajectory inference to characterize B-cells in HIV-1- or HIV-2-infected and in HIV seronegative individuals. We observed increased frequencies of clusters containing hyperactivated T-bet high CD95 high CD27 int and proliferating T-bet + CD95 high CD27 + CD71 + memory B-cells in viremic HIV-1 ( p < 0.001 and p < 0.001, respectively), viremic HIV-2 ( p < 0.001 and p = 0.014, respectively) and in treatment-naïve aviremic HIV-2 ( p = 0.004 and p = 0.020, respectively)-infected individuals, compared to seronegative individuals. In contrast, these expansions were not observed in successfully treated HIV-1-infected individuals. Finally, pseudotime trajectory inference showed that T-bet-expressing hyperactivated and proliferating memory B-cell populations were located at the terminal end of two trajectories, in both HIV-1 and HIV-2 infections. As the treatment-naïve aviremic HIV-2-infected individuals, but not the successfully ART-treated HIV-1-infected individuals, showed B-cell perturbations, our data suggest that aviremic HIV-2-infected individuals would also benefit from antiretroviral treatment.

Spiroindolines represent a privileged structure in medicinal chemistry, although stereocontrol around the spirocarbon can be a synthetic challenge. Here we present a palladium(0)-catalyzed intramolecular Mizoroki-Heck annulation reaction from ( + )-Vince lactam-derived cyclopentenyl-tethered 2-bromo- N -methylanilines for the formation of N -methylspiroindolines. A series of 14 N -methylspiroindolines were synthesized in 59-81% yield with diastereoselectivity >98%, which was rationalized by density functional theory calculations and confirmed through X-ray crystallography. One spiroindoline was converted to an N- and C-terminal protected rigidified unnatural amino acid, which could be orthogonally deprotected., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DR int/high ), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1 high , TIGIT high ) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Scharf, Pedersen, Johansson, Lindman, Olsen, Buggert, Wilhelmson, Månsson, Esbjörnsson, Biague, Medstrand, Norrgren, Karlsson, Jansson and the SWEGUB CORE Group.)

A series of meta-substituted acetophenone derivatives, encompassing N-(alkyloxycarbonyl)thiophene sulfonamide fragments have been synthesized. Several selective AT2 receptor ligands were identified, among those a tert-butylimidazole derivative (20) with a K i of 9.3 nM, that demonstrates a high stability in human liver microsomes (t ½ = 62 min) and in human hepatocytes (t ½  = 194 min). This methyloxycarbonylthiophene sulfonamide is a 20-fold more potent binder to the AT2 receptor and is considerably more stable in human liver microsomes, than a previously reported and broadly studied structurally related AT 2 R prototype antagonist 3 (C38). Ligand 20 acts as an AT 2 R agonist and caused an AT 2 R mediated concentration-dependent vasorelaxation of pre-contracted mouse aorta. Furthermore, in contrast to imidazole derivative C38, the tert-butylimidazole derivative 20 is a poor inhibitor of CYP3A4, CYP2D6 and CYP2C9. It is demonstrated herein that smaller alkyloxycarbonyl groups make the ligands in this series of AT 2 R selective compounds less prone to degradation and that a high AT2 receptor affinity can be retained after truncation of the alkyloxycarbonyl group. Binding modes of the most potent AT 2 R ligands were explored by docking calculations combined with molecular dynamics simulations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Female sex workers (FSW) are considered a key group for HIV transmissions in sub-Saharan Africa. The HIV Care Continuum and HIV drug resistance (HIVDR) among FSW has not been well studied in most countries in West Africa. In the current study we describe the HIV Care continuum and prevalence of HIVDR among FSW in Guinea-Bissau., Methods: A venue-based recruitment and peer-referral of FSW was used in seven cities in Guinea-Bissau from October 2014 to September 2017. We administered a questionnaire, performed discriminatory HIV-testing and collected blood specimens for CD4 count, viral load and HIVDR genotyping., Results: The survey included 440 FSW. The overall HIV-prevalence among FSW was 26.8%. Of the HIV-1 (HIV-1 single- or dually HIV-1/HIV-2) infected FSW (N = 104), 58.7% were previously diagnosed with HIV-1 at enrolment and 41.4% reported taking antiretroviral therapy (ART) compared to 28.6% of the HIV-2 single-infected FSW (N = 14). Among HIV-1 infected FSW on ART (N = 43), 55.8% were virally suppressed (< 1000 copies/ml) and of all HIV-1 infected FSW, 29.8% were virally suppressed. Among ART experienced FSW (N = 22), 50.0% had HIVDR. HIVDR was also found in 9.4% of treatment naïve FSW (N = 53)., Conclusion: The majority of FSW who knew their HIV status received ART, however a large proportion of FSW were not aware of their HIV positive status. This translated into a great majority of the HIV-infected FSW not being virally suppressed. Amongst treatment naïve FSW nearly a tenth had HIVDR, suggesting that sexual transmission of HIVDR is occurring in this at-risk-population.

Two HIV virus types exist: HIV-1 is pandemic and aggressive, whereas HIV-2 is confined mainly to West Africa and less pathogenic. Despite the fact that it has been almost 40 years since the discovery of AIDS, there is still no cure or vaccine against HIV. Consequently, the concepts of functional vaccines and cures that aim to limit HIV disease progression and spread by persistent control of viral replication without life-long treatment have been suggested as more feasible options to control the HIV pandemic. To identify virus-host mechanisms that could be targeted for functional cure development, researchers have focused on a small fraction of HIV-1 infected individuals that control their infection spontaneously, so-called elite controllers. However, these efforts have not been able to unravel the key mechanisms of the infection control. This is partly due to lack in statistical power since only 0.15% of HIV-1 infected individuals are natural elite controllers. The proportion of long-term viral control is larger in HIV-2 infection compared with HIV-1 infection. We therefore present the idea of using HIV-2 as a model for finding a functional cure against HIV. Understanding the key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection could provide novel insights in developing functional HIV cures and vaccines.

Background: Being able to discriminate between HIV-1, HIV-2 and HIV-1/2 dual infection is imperative for the appropriate selection of antiretroviral therapy (ART) in regions with high HIV-2 endemicity., Objectives: To evaluate Bio-Rad Geenius HIV-1/2 Confirmatory Assay against INNO-LIA HIV 1/2 Score and ImmunoComb HIV 1/2 BiSpot with an emphasis towards ability to discriminate between HIV-1, HIV-2 and HIV-1/2 dual infection., Material and Methods: 131 samples from ART naïve HIV infected patients in Guinea-Bissau were selected retrospectively and tested with Geenius, INNO-LIA and Immunocomb. HIV-1/2 RNA were measured in all samples and HIV-1/2 DNA in 59 samples., Results: The Geenius reader typed 62 samples as HIV-1 reactive, 37 samples as HIV-2 reactive and 32 samples as HIV-1/2 dually reactive. Geenius manual reading classified 10% more samples as HIV-1/2 dually reactive (n = 35). INNO-LIA typed 63 samples as HIV-1 reactive, 36 samples as HIV-2 reactive and 32 samples as HIV-1/2 dually reactive while Immunocomb classified a large proportion of samples as HIV-1/2 dually reactive (n = 45). The measurement of agreement of the Geenius reader compared with INNO-LIA and Immunocomb was 92.4% and 84.0% respectively while the measurement of agreement of Geenius manual reading compared with INNO-LIA and Immuncomb was 93.1% and 89.3% respectively., Conclusions: Geenius has similar performance characteristics as INNO-LIA, and performs considerably better than Immunocomb, for differentiating between HIV types. This is especially true when using the Geenius reader while manual reading of the Geenius assay seemed to overestimate the numbers of HIV-1/2 dually reactive samples., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT 2 R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT 2 R antagonist C38 , generating small but significant shifts in AT 2 R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT 2 R as compared to C38 . The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT 2 R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

Background: HIV type 2 (HIV-2) is considered more benign and has fewer pathogenic consequences than HIV type 1 (HIV-1) for most infected individuals. However, reliable estimates of time to AIDS and mortality among those with HIV-2 infection are absent. We therefore aimed to compare the time to AIDS and mortality, and the CD4 T-cell dynamics between those infected with HIV-1 and HIV-2., Methods: We did a prospective open cohort study. We included all police officers with regular employment from police stations in both urban and rural areas of Guinea-Bissau since Feb 6, 1990. We continued to include participants until Sept 28, 2009, and follow-up of HIV-1-positive and HIV-2-positive individuals continued until Sept 28, 2013. We collected blood samples at enrolment and at scheduled annual follow-up visits at police stations. We analysed longitudinal data from individuals infected with HIV-1 and HIV-2 according to time to AIDS, time to death, and T-cell dynamics. Time of HIV infection was estimated as the mid-timepoint between last HIV-seronegative and first HIV-seropositive sample. Data from an additional 2984 HIV-uninfected individuals from the same population were analysed to assess the effect of natural mortality on HIV-related mortality., Findings: 872 participants tested HIV positive during the 23-year study period: 408 were infected with HIV-1 (183 infected before and 225 infected after enrolment) and 464 were infected with HIV-2 (377 before and 87 after enrolment). The median time from HIV infection to development of AIDS was 6·2 years (95% CI 5·4-7·1) for HIV-1 infection and 14·3 years (10·7-18·0) for HIV-2 infection (p<0·0001). The median survival time after HIV infection was 8·2 years (95% CI 7·5-8·9) for HIV-1 infection and 15·6 years (12·0-19·2) for HIV-2 infection (p<0·0001). Individuals who were infected with HIV-1 or HIV-2 before enrolment showed similar results. Comparison with uninfected individuals indicated limited confounding contribution from natural mortality. Mean CD4 percentages were higher in individuals with HIV-2 than in those with HIV-1 during early infection (28·0% [SE 1·3] vs 22·3% [1·7]; p=0·00094) and declined at a slower rate (0·4% [0·2] vs 0·9% [0·2] per year; p=0·028). HIV-2-infected individuals developed clinical AIDS at higher mean CD4 percentages (18·2%, IQR 7·2-25·4) than HIV-1-infected individuals (8·2%, 3·0-13·8; p<0·0001)., Interpretation: Our results show that both HIV-1-infected and HIV-2-infected individuals have a high probability of developing and dying from AIDS without antiretroviral treatment., Funding: Swedish International Development Agency, Swedish Research Council, Swedish Society of Medical Research, Medical Faculty at Lund University, and Region Skåne Research and Development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: With increased access to antiretroviral treatment (ART) in sub-Saharan Africa emergence of HIV-1 pretreatment drug resistance constitutes a serious risk. This may lead to rapid virological failure in subjects initiating ART, and mother-to-child transmission despite prophylaxis., Methods: Treatment-naïve pregnant women from four antenatal care clinics in Bissau, Guinea-Bissau, were enrolled from October 2016 to November 2017. Genotypic resistance testing and phylogenetic subtype analysis was performed on 48 specimens., Results: Forty eight women met the survey inclusion criteria. All specimens were successfully amplified and genotyped. Specimens from five women were associated with HIV-1 drug resistance mutations. Four carried mutations exclusively linked to non-nucleoside reverse transcriptase inhibitors (NNRTIs) (K103N, K103N/S) and one carried mutations to both NNRTIs (G190S, K101E) and nucleoside reverse transcriptase inhibitors (NRTIs) (M184V). These results corresponded to 10.4% (95% CI: 4.5-22.2%), 2.1% (95% CI: 0.4-10.9%) and 0% (95% CI: 0.0-7.4%) drug resistance mutations to NNRTIs, NRTIs and protease inhibitors, respectively. HIV-1 circulating recombinant form 02AG was most commonly found, followed by HIV-1 sub-subtype A3. Subtype/CRF was not associated with drug resistance mutations., Conclusion: Our study reports a 10.4% prevalence of pretreatment drug resistance to NNRTIs in HIV-1-infected pregnant women in the capital Bissau, Guinea Bissau. Since NNRTIs are part of first-line ART in the country, baseline resistance screenings or adjustment of national treatment guidelines should be considered as antiretroviral treatment programs are scaled up., Competing Interests: The authors have declared that no competing interests exist.

Microtubules can regulate GPCR (G protein-coupled receptor) signaling in various cell types. In vascular smooth muscle, activation of the β-adrenoceptor leads to production of cAMP to mediate a vasorelaxation. Little is known about the role of microtubules in smooth muscle, and given the importance of this pathway in vascular smooth muscle cells, we investigated the role of microtubule stability on β-adrenoceptor signaling in rat renal and mesenteric arteries. In isometric tension experiments, incubation with the microtubule inhibitors colchicine and nocodazole enhanced isoprenaline-mediated relaxations of renal and mesenteric arteries that the microtubule stabilizer, paclitaxel, prevented. Sharp microelectrode experiments showed that colchicine treatment caused increased hyperpolarization of mesenteric artery segments in response to isoprenaline. Application of the Kv7 channel blocker, XE991, attenuated the effect of colchicine on isoprenaline relaxations, whereas iberiotoxin-a BKCa channel blocker-had no effect. In addition, colchicine improved the relaxations to the Kv7.2 to 7.5 activator, S-1, in both renal and mesenteric artery segments compared with dimethyl sulfoxide incubation. We determined that increased mesenteric artery myocytes treated with colchicine showed increased Kv7.4 membrane expression, but Western blot analysis showed no change in total Kv7.4 protein. This study is the first to show microtubule disruption improves the β-adrenoceptor-mediated relaxations of mesenteric and renal arteries and determine this enhancement to be because of increased membrane expression of the Kv7 voltage-gated potassium channels., (© 2017 American Heart Association, Inc.)

Empirical force fields for computer simulations of carbohydrates are often implicitly assumed to be valid also at temperatures different from room temperature for which they were optimized. Herein, the temperature dependence of the hydroxymethyl group rotamer populations in short oligosaccharides is investigated using molecular dynamics simulations and NMR spectroscopy. Two oligosaccharides, viz., methyl β-cellobioside and β-cellotetraose were simulated using three different carbohydrate force fields (CHARMM C35, GLYCAM06, and GROMOS 56Acarbo) in combination with different water models (SPC, SPC/E, and TIP3P) using replica exchange molecular dynamics simulations. For comparison, hydroxymethyl group rotamer populations were investigated for methyl β-cellobioside and cellopentaose based on measured NMR (3)JH5,H6 coupling constants, in the latter case by using a chemical shift selective NMR-filter. Molecular dynamics simulations in combination with NMR spectroscopy show that the temperature dependence of the hydroxymethyl rotamer population in these short cellooligomers, in the range 263-344 K, generally becomes exaggerated in simulations when compared to experimental data, but also that it is dependent on simulation conditions, and most notably properties of the water model.

Objectives: The purpose of this cross-sectional study was to determine the prevalence of hoarseness in children attending the first or second grade of primary school and to explore possible background factors for hoarseness in children., Methods: The participants were 217 children, aged 6-10 years, from 10 different schools. Questionnaires were filled in by the parents and the teachers of the children and voice samples were recorded. The voice samples from the children were perceptually evaluated by eight trained listeners and intra- and inter-rater reliability was calculated. Additionally, the parents and teachers were in the questionnaires asked to rate the children's voices. Connections between background factors and voice quality were explored., Results: Both the intra- and inter-rater reliability for the trained listeners were relatively high and significant. The prevalence of hoarseness for the whole group was 12.0% as judged by the trained listeners. For girls, the prevalence of hoarseness was 7.8% and for boys 15.8%. A lower teacher rating of degree of maturity correlated significantly with the voice quality. Additionally, there was a significant negative correlation between the amount of talking at home and voice quality. For girls, heavy voice use as an infant correlated significantly with voice quality. For boys, being the youngest sibling correlated significantly with voice quality., Conclusions: The results from the present study indicate that more attention should be paid to hoarseness in children and that background factors should be further explored., (Copyright © 2015 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma is an aggressive and highly lethal disease frequently characterized by a dense stromal or desmoplastic response. Accumulating evidence exists that tumor desmoplasia plays a central role in disease progression and that e.g. activated pancreatic stellate cells (PSCs) are responsible for the excess matrix production. The mechanisms underlying the tumor versus stroma interplay are complex. Pancreatic cancer cells release mitogenic and fibrogenic stimulants, such as transforming growth factor β(1), platelet-derived growth factor (PDGF), sonic hedgehog, galectin 3, endothelin 1 and serine protease inhibitor nexin 2, all of which may promote the activated PSC phenotype. Stellate cells in turn secrete various factors, including PDGF, stromal-derived factor 1, epidermal growth factor, insulin-like growth factor 1, fibroblast growth factor, secreted protein acidic and rich in cysteine, matrix metalloproteinases, small leucine-rich proteoglycans, periostin and collagen type I that mediate effects on tumor growth, invasion, metastasis and resistance to chemotherapy. This review intends to shed light on the mechanisms by which PSCs in the stroma influence pancreatic cancer development. The increased understanding of this interaction will be of potential value in designing new modalities of targeted therapy. and IAP., (Copyright © 2011 S. Karger AG, Basel.)

One of the challenges of interpreting a Quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) analysis is examining the sensitivity of conclusions that may be drawn to varying values of the utility coefficients for days with toxicity and days after disease progression. We present a graphic that parsimoniously displays the impact on median Q-TWiST survival across treatment groups of varying values of the utility coefficients. The goal of the graphic is to present a concise Q-TWiST analysis. We use Zhao and Tsiatis (Biometrika 1997; 84(2): 339-348) to adjust for the bias in Kaplan-Meier (K-M) estimates. The graphic contains bounds that approximate points for which statistical significance would be achieved by comparing the median Q-TWiST survival between treatment alternatives for each value of the utility coefficients. The plot may be generalized to compare Q-TWiST means, medians or percentiles across treatment groups. We demonstrate the application of the Q-TWiST plot through a re-analysis of a randomized phase III North Central Cancer Treatment Group (NCCTG) clinical trial of recombinant Interferon-2alpha in patients with malignant melanoma. We explore alternative options to customize the graphic representation for other data sets drawn from several NCCTG clinical trials.

Background: Payment for care provided as part of clinical research has become less predictable as a result of managed care. Because little is known at present about how entry into cancer trials affects the cost of care for cancer patients, we conducted a matched case-control comparison of the incremental medical costs attributable to participation in cancer treatment trials., Methods: Case patients were residents of Olmsted County, MN, who entered phase II or phase III cancer treatment trials at the Mayo Clinic from 1988 through 1994. Control patients were patients who did not enter trials but who were eligible on the basis of tumor registry matching and medical record review. Sixty-one matched pairs were followed for up to 5 years after the date of trial entry for case patients or from an equivalent date for control patients. Hospital, physician, and ancillary service costs were estimated from a population-based cost database developed at the Mayo Clinic., Results: Trial enrollees incurred modestly (no more than 10%) higher costs over various follow-up periods. The mean cumulative 5-year cost in 1995 inflation-adjusted U.S. dollars among trial enrollees after adjustment for censoring was $46424 compared with $44 133 for control patients. After 1 year, trial enrollee costs were $24645 compared with $23 964 for control patients., Conclusions: This study suggests that cancer chemotherapy trials may not imply budget-breaking costs. Cancer itself is a high-cost illness. Clinical protocols may add relatively little to that cost.

Providing current information related to infectious disease transmission to child care providers is a challenge for medical and public health practitioners. Because systems that deliver and support child care are so diverse, sharing information within and across various disciplines is problematic. While some resources do exist, there is a need for a national dissemination system that provides current and comprehensible information to child care providers and the families they serve. In the meantime, there is much a primary health provider can do to support parents and providers in their child-caring relationship and to promote the health and welfare of the children in care.