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Purpose:Mistletoe extract (ME) is widely used for patients with cancer to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration.Materials and Methods:This phase I trial of intravenous mistletoe (Helixor M) aimed to determine the recommended phase II dosing and to evaluate safety. Patients with solid tumor progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL.Results:Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The MTD was 600 mg. Treatment-related adverse events (AE) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in 3 patients (14.8%). Stable disease was observed in 5 patients who had one to six prior therapies. Reductions in baseline target lesions were observed in 3 patients who had two to six prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by Functional Assessment of Cancer Therapy-General increased from 79.7 at week 1 to 93 at week 4.Conclusions:Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted.Significance:Although ME is widely used for cancers, its efficacy and safety are uncertain. This first phase I trial of intravenous mistletoe (Helixor M) aimed to determine phase II dosing and to evaluate safety. We recruited 21 patients with relapsed/refractory metastatic solid tumor. Intravenous mistletoe (600 mg, 3/week) demonstrated manageable toxicities (fatigue, nausea, and chills) with disease control and improved QoL. Future research can examine ME's effect on survival and chemotherapy tolerability.

This article aims to assess the Integrated Development Planning (IDP) process for improved community participation. The IDP process was developed to improve strategic planning and community participation at the municipal level. Many South African municipalities have been struggling to use the IDP process to improve community participation. The methodology included 400 respondents who were chosen through a probability sampling technique and probed to complete the online survey using a closed-ended questionnaire guide, and ten respondents were also chosen through a non-probability sampling technique and were face-to-face interviewed using a semi-structured interview guide. The key findings revealed that poor community participation exists in the study area due to a lack of encouragement from responsible authorities. The Tzaneen municipality does not provide adequate feedback to the communities, and the inputs of the communities are not considered. There is a continuous lack of community consultation during the annual review of the IDP. The ineffective IDP process for improved community participation presents several challenges. Thus, this article concluded by providing a few recommendations to enhance the application of the IDP process and community participation. The Tzaneen municipal area should at all times uphold democratic principles by ensuring active public participation, transparency, and openness in municipal affairs. It also recommends making it easier for marginalised and previously disadvantaged people to participate in municipal policy and decision-making without prejudice. South African municipalities, including Tzaneen municipality, should develop and innovate institutional, and organisational capabilities to better utilise their resources, mitigate socio-economic challenges and enhance service delivery.

The cervix is the gateway to the upper female reproductive tract, connecting the uterus and vagina. It plays crucial roles in fertility and pregnancy maintenance from onset until delivery of the fetus, and prevents pathogen ascension. Compromised functionality of the cervix can lead to disorders, including infertility, chronic infections and cancers. The cervix comprises two regions: columnar epithelium-lined endocervix and stratified squamous epithelium-lined ectocervix, meeting at the squamocolumnar transition zone. So far, two-dimensional cultures of genetically unstable immortalized or cancer cell lines have been primarily used to study cervix biology in vitro. The lack of an in vitro system that reflects the cellular, physiological and functional properties of the two epithelial types has hampered the study of normal physiology, disease development and infection processes. Here we describe a protocol for cell isolation, establishment, long-term culture and expansion of adult epithelial stem cell-derived endocervical and ectocervical organoids from human biopsies and mouse tissue. These two organoid types require unique combinations of growth factors reminiscent of their in vivo tissue niches and different culturing procedures. They recapitulate native three-dimensional tissue architecture and patterning. The protocol to generate these organoids takes 4-6 weeks. We also describe procedures to introduce human papillomavirus oncogenes into the cervical stem cells by genetic manipulation to model cervical cancer and infection of the organoids with the highly prevalent sexually transmitted bacterial pathogen Chlamydia trachomatis. These organoid systems open new possibilities to study cervix biology, infections and cancer evolution, and have potential applications in personalized medicine, drug screening, genome editing and disease modeling.

To determine the usefulness of mid-urethral slings (MUS) in the surgical management of women presenting with urinary stress incontinence (USI) METHOD: A consensus committee of multidisciplinary experts (CUROPF) was convened and focused on PICO questions concerning the efficacy and safety of MUS surgery compared to other procedures and concerning which approach (retropubic (RP) vs transobturator (TO)) should be proposed as a first-line MUS surgery for specific subpopulations (obese; intrinsic sphincteric deficiency (ISD); elderly) RESULTS: As compared to other procedures (urethral bulking agents, traditional slings and open colposuspension), the MUS procedure should be proposed as the first-line surgical therapy (strong agreement). MUS surgery can be associated with complications and proper pre-operative informed consent is mandatory (strong agreement). Mini-slings (SIS/SIMS) should only be proposed in clinical trials (strong agreement). Both RP and TO approaches may be proposed for the insertion of MUS (strong agreement). However, if the woman is willing to accept a moderate increase in per-operative risk, the RP approach should be preferred (strong agreement) since it is associated with higher very long-term cure rates and as it is possible to completely remove the sling surgically if a severe complication occurs. The RP approach should be used for the insertion of MUS in a woman presenting with ISD (strong agreement). Either the RP or TO approach should be used for the insertion of MUS in an obese woman presenting with USI (strong agreement). In very obese women (BMI ≥35-40kg/m

Global climate change is altering the frequency, intensity, and timing of drought and late-spring frost (LSF). European beech, an ecological and economical cornerstone of European forestry, has been shown to be susceptible to both extremes. Since recovery from both drought and frost damage requires access to stored carbohydrate reserves, the joint occurrence of drought and late-frost exacerbates the deleterious effects on forest health. Both extremes are projected to increase in frequency with increasing temperatures, yet, a statistical model for compound drought and late-spring frost events over time is still lacking. Thus, in order to facilitate forest risk assessment, we quantify the joint probability of drought and spring late-frost risk in the historic domain and identify shifts in this dependency across multiple, future climate change scenarios. Analogously, we determine the individual probability of both drought and LSF to determine the contribution of each extreme to the joint probability. We determine frost risk based on the minimum temperature during the period of leaf flushing as predicted by a phenological model. Drought risk is quantified using the Standardized Precipitation Evapotranspiration Index (SPEI). To quantify the joint risk of these two extremes while accounting for climatic and topographical covariates, we use vine copula based models. Specifically, we apply a novel, regular vine copula based regression model, Y-vine copula regression, designed for a two-response regression setting.We establish a historical baseline for the joint probability of drought and LSF and identify critical climatic and topographic covariates. Subsequently, we repeat the analysis with climate projections for three different scenarios (RCP 2.6, RCP 4.5, RCP 8.5). We identify differences in the joint probability of drought and LSF across the three climate change trajectories, yet note, that the critical covariates remain constant across scenarios. To further disentangle the coupling between drought and LSF, we use a single response, D-vine copula to determine probability and critical covariates for each extreme separately. Consequently, we are able to determine whether the risk of frost and drought change in concert, how this differs between climate change scenarios, and which covariates drive each extreme.

Besides offering numerous important ecosystem services, sustainably managed forests can help reduce atmospheric CO2 concentrations and thus mitigate climate change. Forest-based mitigation occurs through the carbon sink in the forest itself, the carbon sink in wood products, and through substitution effects when wood products replace carbon-intensive materials and fuels.The relative importance of each of these three mitigation dimensions depends on a multitude of factors. First, forest type and structure, site conditions, and climate change and associated disturbances determine the amount of carbon that may be sequestered over the next decades at a given site. Second, the type and intensity of management determines the trade-off between on-site carbon sequestration and carbon storage in wood products. Third, management, wood usage patterns, and the carbon-intensity of the economy determine the amount of avoided emissions via substitution effects.To assess their impact on the total forest mitigation potential, we conducted a factorial modeling experiment by varying all of the aforementioned factors. Specifically, we looked at the forest type (needle-leaved vs broad-leaved) and age (young vs mature), increased and decreased harvest intensities, increased material wood usage and cascading, decarbonization rates, climate change and disturbance scenarios, and salvage logging practices after disturbance.Under an assumed "closer-to-nature forest management" our results show a higher mitigation potential of young forests compared to mature forests, whereas the forest type does not have a clear effect. The importance of substitution effects outweighs the importance of the forest and product carbon sink on shorter time scales. This changes towards the end of the century, assuming that substitution effects decrease because the substituted materials can be produced in a less carbon-intensive way. Increases in harvest intensity consequently are also only beneficial for climate change mitigation on these shorter time scales, though they likely have adverse effects on other ecosystem services. Our results also show that increased material usage (as opposed to energy usage) of wood can be an important lever for mitigation. Finally, changes in disturbances strongly affect the mitigation potential, though the mitigation impact of a subsequent salvaging operation heavily depends on the forest type and the product portfolio created from the salvaged wood.In conclusion, our results quantify the impacts and interactions of the different factors that govern forest-based mitigation, while highlighting the complexity of the topic and the importance of the considered time-scales.

Aim Recurrence of hiatal hernia may occur in up to 70% of patients. Failure is defined subjectively as recurrence of symptoms and objectively by imaging or pH studies, which can diagnose recurrent hiatal hernia, wrap disruption, and/or reflux disease. Approximately 25% of patients need partial or subtotal esophagectomy - mainly secondarily to scar formation and fibrosis at the hiatus site. Our aim is to report the early results of a novel double tract reconstruction in treating failed re-do fundoplication Materials and methods Retrospective review of prospectively collected data on patients who had undergone salvage operation of failed re-do fundoplication related to demographics, operative details, surgical and clinical outcomes as well as patient satisfaction. Results Conclusion Double tract reconstruction appears a suitable option in treating symptomatic recurrently failed hiatal hernia repair especially after the second or third recurrence with disruption of the anatomy and scarring of gastroesophageal junction.

Aim Patients with symptomatic umbilical hernia with associated rectus diastasis represent an increasing clinical problem. The objective was to analyze feasibility and safety using a novel surgical approach: laparoscopic extraperitoneal endoscopic staple-based sublay operation (LEESS). Methods Observational study with all patients for patients who underwent LEESS and a minimum follow-up of 1 year. Data was obtained from a prospective mantained database at Herniamed Registry Results 81 patients were operated from January 1, 2016, to June 30, 2020. Mean operative time was 100 (range, 15–200) min and mean length of hospital stay was 5 (range, 1–9) days. The overall 30 days postoperative morbidity was 12.34%: 2 (2.4%) developed a symptomatic subfascial seroma (minor complication); 2 (2.4%), a postoperative bleeding; 2 (2.4%), mild wound infection without mesh infection; and 1 (1.23%) of internal herniation through a defect in the posterior rectus sheath suture line. There were no surgery-related deaths (in-hospital mortality, 0). After a total follow-up of 12 months, 54 patients out of 81 (rate, 69.3%) recorded their information in the registry; 9 (16.7%) reported pain. The ratio of “Pain at rest” (5.6%) was significantly less than preoperatively (58.8%; p Conclusion The LEESS technique with mesh augmentation appears to be an innovative, minimally invasive, feasible and safe surgical procedure for treatment of patients with symptomatic ventral midline hernia

BackgroundEpigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronicHelicobacter pyloriinfections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail.ResultsHere, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics.

Table S3 shows reasons for discontinuation with patient charateristics