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Background Tenofovir alafenamide (TAF), a prodrug of tenofovir (TFV), is included in the majority of the recommended first-line antiretroviral regimens for patients living with human immunodeficiency virus (HIV), but there are limited data on TAF use in pregnant women. We aimed to examine the plasma pharmacokinetics of TAF and TFV in pregnant women from Europe. Methods Pregnant women living with HIV were included from treatment centers across Europe, and intensive pharmacokinetic sampling in the third trimester and postpartum was performed. Pharmacokinetic parameters of TAF and TFV were determined with noncompartmental analysis. The proportion of women with a TAF area under the curve (AUClast) below the target of 53.1 ng∗h/mL was determined. Clinical efficacy and safety outcome parameters were reported. Results In total, 20 pregnant women living with HIV were included. At the third trimester, geometric mean TAF AUClast and Cmax were decreased by 46% and 52%, respectively, compared with postpartum. TFV AUC0-24h, Cmax, and Ctrough decreased by 33%, 30%, and 34%, respectively. The proportion of women with a TAF AUClast 50 copies/mL at third trimester and no mother-to-child transmission occurred. Conclusions TAF plasma concentrations were reduced by about half in women living with HIV during third trimester of pregnancy but remained above the predefined efficacy target in the majority of the pregnant women. TFV concentrations were reduced by approximately 30% during third trimester. Despite the observed exposure decrease, high virologic efficacy was observed in this study.

Invasive cervical cancer (ICC) is associated in nearly 100% with persistent high-risk Human Papillomavirus (HR-HPV) infection. ICC is still one of the leading causes for cancer mortality in women worldwide. The immunosuppressive influence of Human Immunodeficiency Virus (HIV) and the immunocompromised period of pregnancy due to tolerance induction against the hemiallogeneic fetus, are generally risk factors for acquisition and persistence of HR-HPV infections and their progression to precancerous lesions and HPV-associated carcinoma.Overall, 81 pregnant women living with HIV (WLWH) were included. A medical history questionnaire was used to record clinical and HIV data. Participants received cervicovaginal cytological smear, colposcopy and HPV testing. HPV test was performed using BSGP5+/6+ PCR with Luminex read-out. The HR-HPV genotypes 16, 18, 31, 33, 45, 52, 58 were additionally grouped together as high-high-risk HPV (HHR-HPV) for the purpose of risk-adapted analysis.HR-HPV prevalence was 45.7%. Multiple HPV infections were detected in 27.2% of participants, of whom all had at least one HR-HPV genotype included. HR-HPV16 and HR-HPV52 were the most prevalent genotypes and found when high squamous intraepithelial lesion (HSIL) was detected by cytology. HIV viral load of ≥ 50 copies/ml was associated with higher prevalence of HR-HPV infections. Whereas, CD4 T cells 350/µl showed association with occurrence of multiple HPV infections. Time since HIV diagnosis seemed to impact HPV prevalence.Pregnant WLWH require particularly attentive and extended HPV-, colposcopical- and cytological screening, whereby clinical and HIV-related risk factors should be taken into account.

Adenovirus-mediated combination gene therapies have shown promising results in vaccination or treating malignant and genetic diseases. Nevertheless, an efficient system for the rapid assembly and incorporation of therapeutic genes into high-capacity adenoviral vectors (HCAdVs) is still missing. In this study, we developed the iMATCH (integrated modular assembly for therapeutic combination HCAdVs) platform, which enables the generation and production of HCAdVs encoding therapeutic combinations in high quantity and purity within 3 weeks. Our modular cloning system facilitates the efficient combination of up to four expression cassettes and the rapid integration into HCAdV genomes with defined sizes. Helper viruses (HVs) and purification protocols were optimized to produce HCAdVs with distinct capsid modifications and unprecedented purity (0.1 ppm HVs). The constitution of HCAdVs, with adapters for targeting and a shield of trimerized single-chain variable fragment (scFv) for reduced liver clearance, mediated cell- and organ-specific targeting of HCAdVs. As proof of concept, we show that a single HCAdV encoding an anti PD-1 antibody, interleukin (IL)-12, and IL-2 produced all proteins, and it led to tumor regression and prolonged survival in tumor models, comparable to a mixture of single payload HCAdVs in vitro and in vivo. Therefore, the iMATCH system provides a versatile platform for the generation of high-capacity gene therapy vectors with a high potential for clinical development., Graphical Abstract, The iMATCH platform enables an efficient assembly of up to four orthogonal expression cassettes on a single plasmid from which high-capacity adenoviral vectors can be generated within 3 weeks in unprecedented purity. iMATCH vectors encoding immunotherapeutic combinations led to tumor regression and prolonged survival, comparable to mixtures of single payload HCAdVs.

Burn wound progression (BWP) leads to vertical and horizontal injury extension. The “burn comb model” is commonly used, in which a full-thickness burn with intercalated unburned interspaces is induced. We aimed to establish an injury progressing to the intermediate dermis, allowing repeated wound evaluation. Furthermore, we present a new dorsal frame that enables topical drug application. Eight burn fields and six interspaces were induced on each of 17 rats’ dorsa with a 10-second burn comb application. A developed 8-panel aluminum frame was sutured onto 12 animals and combined with an Elizabethan collar. Over 14 days, macroscopic and histologic wound assessment and laser speckle contrast imaging (LSCI) were performed besides evaluation of frame durability. The 10-second group was compared with nine animals injured with a full-thickness 60-second model. Frame durability was sufficient up to day 4 with 8 of the 12 frames (67%) still mounted. The 60-second burn led to an increased extent of interspace necrosis (P = .002). The extent of necrosis increased between days 1 and 2 (P = .001), following the 10-second burn (24% ± SEM 8% to 40% ± SEM 6%) and the 60-second burn (57% ± SEM 6% to 76% ± SEM 4%). Interspace LSCI perfusion was higher than burn field perfusion. It earlier reached baseline levels in the 10-second group (on day 1: 142% ± SEM 9% vs 60% ± SEM 5%; P < .001). Within day 1, the 10-second burn showed histological progression to the intermediate dermis, both in interspaces and burn fields. This burn comb model with its newly developed fixed dorsal frame allows investigation of topical agents to treat BWP in partial-thickness burns.

Exclusive breastfeeding is recommended for women living with HIV (WLWH) in low-income-but not in high-income-countries, where milk substitutes are preferred. Some guidelines for high-income countries opted for a shared decision-making process regarding breastfeeding in optimal scenarios with adherence to antiretroviral therapy (cART), suppressed maternal viral load (mVL), and clinical monitoring. Although vertical transmission (VT) risk under cART is estimated below 1% in low-income settings, data from high-income countries are rare.We retrospectively analyzed all 181 live births from WLWH at the LMU Munich university hospital perinatal center in Germany between January 2016 and December 2020. We focused on VT, suppressed mVL and optimal scenario rates, breastfeeding frequency, cART regimens, and infant prophylaxis. All women were counseled according to current guidelines, foremost recommending avoidance of breastfeeding.In the 5-year cohort, no VT was observed. One hundred fifty-one WLWH (83.4%) decided not to breastfeed, even in optimal scenarios. Thrity infants (16.6%) were nursed, of which 25 were within an optimal scenario, whereas in 5 cases, breastfeeding was performed with a detectable VL in pregnancy or the postpartum period. All WLWH were treated with cART at delivery, and 91.7% sustained suppressed mVL. Zidovudine infant prophylaxis was given between 2 and 8 weeks but not necessarily over the whole breastfeeding duration and was declined from 5 breastfeeding WLWH.Although the cohort is too small to assess VT risk through breastfeeding with cART-suppressed mVL, breastfeeding might be an alternative even in high-income countries, but further studies are needed.

Mastic asphalt (MA) is an important construction material mainly used for infrastructure pavements as well as industrial and garage floors. As mastic asphalt construction sites are often limited in space, the prevalent form of construction is by manual paving. Therefore, the emissions caused by mastic asphalt are not only relevant for the environment, but also highly relevant for workers' health. In this study, we examine four mastic asphalt mixtures in terms of their emissions and worker exposure at various construction temperatures, ranging from 195 °C to 245 °C. We conducted three laboratory studies and a field study to evaluate the emissions away from the construction site, emissions in close proximity to the construction site, direct worker exposure and, for the very first time, also the absolute emissions in mass PM10 a.d. per mass of MA. The experiments show that a big part (80 wt%) of the PM10 a.d. emissions consists of particles smaller than 0.8 μm a.d. and are therefore very health relevant. Furthermore, we could show consistently in all our experiments that decreasing the paving temperature by 50 °C (by using a MA mixture workable below 200 °C) leads to an emission reduction of up to 70%.

Die 30-jahrige Johanna M. sucht ihren Hausarzt auf, da sie seit einem Jahr an vaginalen bakteriellen Infektionen und vermehrtem Ausfluss leidet. Trotz verschiedener Therapien (s. u.) bleiben die Beschwerden — neben Ausfluss auch starkes Brennen — gleich.

Summary Purpose Several operative approaches and various implants for osseous fixation have been described to achieve four-corner fusion of the wrist. Given the discordance and to aid in further standardizing the technique, this study directly compares the outcomes of K-wire, fusion plate, and headless retrograde compressive screw fixations to achieve four-corner arthrodesis. Methods Sixty-four patients underwent four-corner fusion over a period of 5 years and were reviewed retrospectively. Twenty-one patients underwent bone fixation with conventional K-wires, 26 with locking plates, and 17 patients were treated by headless retrograde compressive screw fixations. Patients of the different groups were comparable regarding age, sex, hand dominance, and stage of disease. Results All study groups showed significant improvements in grip strength, decrease in pain (NRS) at rest and with activity, range-of-motion of the wrist, and wrist function (measured by the DASH-score). When evaluating the three groups amongst each other, overall complication and nonunion rates were low and revealed no significant differences between the groups of patients. However, regarding postoperative NRS at activity, dorsal flexion, and DASH-scores, the "screw" group showed significantly better results than the "wire" group. Conclusion The results show that all examined techniques of four-corner fusion can improve wrist function when compared to preoperative baseline (NRS at rest and activity, postoperative DASH-scores). However, headless retrograde compressive screw fixation had significant better results regarding pain relief (NRS) at activity and postoperative DASH-scores.

It has been shown that pre- and postconditioning of ischemically challenged tissue with erythropoietin (EPO) is able to reduce necrosis in a dose-dependent manner. The aim of this study was to determine the tissue-protective effects of different EPO dosages and administration regimes. Three groups of six C57Bl/6-mice each were analyzed: (1) pre- and postconditioning with initial high doses of EPO (starting at 2500 I.U./kg bw i.p.) followed by low doses of EPO (125 I.U./kg bw i.p.) (EPO-high-dose); (2) pre- and postconditioning with low doses of EPO (125 I.U./kg bw i.p.) (EPO-low-dose); and (3) untreated control group. Randomly perfused musculocutaneous flaps were mounted on dorsal skinfold chambers undergoing acute persistent ischemia and developing ∼50% necrosis without treatment. Intravital epifluorescence microscopy was performed at days 1, 3, 5, 7, and 10 after surgery, assessing flap necrosis, microcirculation, and angiogenesis. The hematocrit was measured at days 0, 3, 7, and 10. Only the EPO-low-dose regimen was associated with a significant reduction of necrosis when compared to untreated controls. EPO-low-dose showed a higher increase in both arteriolar diameter and velocity, thereby resulting in a significantly increased arteriolar blood flow and a hence higher functional capillary density (FCD) of the critically perfused zone. EPO-induced angiogenesis was significantly increased in EPO-low-dose at days 7 and 10. Only EPO-high-dose reached a significant hematocrit increase by day 10. Tissue pre- and postconditioning with low doses of EPO protects the critically perfused musculocutaneous tissue by maintaining capillary perfusion because of increased arteriolar blood flow mediated by nitric oxide (NO) expression.

The composition of high altitude ice clouds is still a matter of intense discussion. The constituents in question are ice and nitric acid hydrates but the exact phase composition of clouds and its formation mechanisms are still unknown. In this work conclusive evidence for a long predicted phase alphanitric acid trihydrate (alpha NAT) is presented. This Phase was characterized by a combination of X ray and Neutron diffraction experiments allowing a convincing structure solution. Furthermore vibrational spectra (infrared and inelastic neutron scattering) were recorded and compared with theoretical calculations. A strong interaction between water ice and alpha NATwas found which explains the experimental spectra and the phase transition kinetics. On the basis of these results we propose a new three step mechanism for NAT formation in high altitude ice clouds.

The composition of high-altitude ice clouds is still a matter of intense discussion. The constituents in question are ice and nitric acid hydrates, but the exact phase composition of clouds and its formation mechanisms are still unknown. In this work, conclusive evidence for a long-predicted phase, alpha-nitric acid trihydrate (alpha-NAT), is presented. This phase was characterized by a combination of X-ray and neutron diffraction experiments, allowing a convincing structure solution. Furthermore, vibrational spectra (infrared and inelastic neutron scattering) were recorded and compared with theoretical calculations. A strong interaction between water ice and alpha-NAT was found, which explains the experimental spectra and the phase-transition kinetics. On the basis of these results, we propose a new three-step mechanism for NAT formation in high-altitude ice clouds.

Temperature reduction of mastic asphalt (MA) mixtures can decrease costs and energy demand, as well as health-relevant emissions of particulate matter throughout the life cycle. A state-of-the-art method for temperature reduction is wax modification of the bituminous binder to reduce its viscosity. In this paper, the results of an extensive study. On mechanical performance, particulate matter emission and life-cycle analysis of temperature-reduced MA are presented. Therefore, a reference MA is compared to three temperature-reduced MAs: a state-of-the-art reduction by modification with amide wax (AW) and an alternative method of substituting crushed aggregates by rounded ones. For both methods, a temperature reduction of 30°C can be realised. In addition, a combination of both methods, wax modification and use of rounded aggregates, is investigated. For this combination a reduction of 50°C is possible. The results show that the resistance to permanent deformation is not decreased by using rounded aggregates and that it can be doubled by employing AW regardless of the aggregate shape. Resistance to low-temperature cracking is not affected by any of the studied methods for temperature reduction. Emission analysis reveals that more than 80% of the emitted particulates are below 2.5 µm a.d. (aerodynamic diameter). From a life-cycle perspective, a main benefit of temperature-reduced MAs is the significant decrease in particulate emissions by up to 80% in case of 50°C temperature reduction. Also, up to 20% of production process energy can be saved when the mixing temperature is reduced by 50°C. Application of a wax additive reduces process energy costs, but increases the total life-cycle costs. Based on the considered scenarios, the application of additives is controversial and the substitution of crushed aggregates by rounded aggregates seems to be beneficial.

The composition of high‐altitude ice clouds is still a matter of intense discussion. The constituents in question are ice and nitric acid hydrates, but the exact phase composition of clouds and its formation mechanisms are still unknown. In this work, conclusive evidence for a long‐predicted phase, alpha‐nitric acid trihydrate (alpha‐NAT), is presented. This phase was characterized by a combination of X‐ray and neutron diffraction experiments, allowing a convincing structure solution. Furthermore, vibrational spectra (infrared and inelastic neutron scattering) were recorded and compared with theoretical calculations. A strong interaction between water ice and alpha‐NAT was found, which explains the experimental spectra and the phase‐transition kinetics. On the basis of these results, we propose a new three‐step mechanism for NAT formation in high‐altitude ice clouds.

Despite profound expertise and advanced surgical techniques, ischemia-induced complications ranging from wound breakdown to extensive tissue necrosis are still occurring, particularly in reconstructive flap surgery. Multiple experimental flap models have been developed to analyze underlying causes and mechanisms and to investigate treatment strategies to prevent ischemic complications. The limiting factor of most models is the lacking possibility to directly and repetitively visualize microvascular architecture and hemodynamics. The goal of the protocol was to present a well-established mouse model affiliating these before mentioned lacking elements. Harder et al. have developed a model of a musculocutaneous flap with a random perfusion pattern that undergoes acute persistent ischemia and results in ~50% necrosis after 10 days if kept untreated. With the aid of intravital epi-fluorescence microscopy, this chamber model allows repetitive visualization of morphology and hemodynamics in different regions of interest over time. Associated processes such as apoptosis, inflammation, microvascular leakage and angiogenesis can be investigated and correlated to immunohistochemical and molecular protein assays. To date, the model has proven feasibility and reproducibility in several published experimental studies investigating the effect of pre-, peri- and postconditioning of ischemically challenged tissue.