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BACKGROUND: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. MATERIALS AND METHODS: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. RESULTS: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. CONCLUSIONS: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

PURPOSE: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. MATERIALS AND METHODS: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. RESULTS: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. CONCLUSIONS: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Objective: Blood pressure variability (BPV) and its potential association with early hematoma expansion (HE) in intracerebral hemorrhage (ICH) remains to be fully elucidated. Our study explores the potential link between BPV within the first 24 h after admission and HE in ICH. Methods: In a prospective cohort single-center study, we analyzed consecutive patients with spontaneous ICH. Continuous BP data via an arterial line extracted from the Intellispace Critical Care and Anesthesia information system (Philips Healthcare) were analyzed over 0–2, 0–8, 0–12, and 0–24 h intervals post-admission. BPV was assessed through successive variability (SV), standard deviation (SD), and coefficient of variation (CV) using all available BP measurements. Early HE was defined as an absolute [≥ 6 ml] or relative [≥ 33 %] increase in ICH volume on 24-hours follow-up brain imaging. Secondary endpoints were the influence of BP on admission and other potential risk factors for HE. Results: Among 305 ICH-patients (mean age ± SD 70.1 ± 14.9 years, 47.9 % female, median NIHSS 6 (3, 13), median ICH score 1 (1, 2)), 41 (13.4 %) experienced HE. HE-patients had higher NIHSS (p = 0.015), ICH-score (p = 0.005), ICH volume (p 30 cm3) experienced lower absolute BP and BPV indices and worse clinical outcomes. These findings suggest a nuanced relationship between BP dynamics and ICH severity, underscoring the need for individualized BP management in acute ICH care. Further research is necessary to explore these relationships and optimize treatment strategies.

Abstract Background Despite known benefits of physical activity in reducing breast cancer risk, its impact on mammographic characteristics remain unclear and understudied. This study aimed to investigate associations between pre-diagnostic physical activity and mammographic features at breast cancer diagnosis, specifically mammographic breast density (MBD) and mammographic tumor appearance (MA), as well as mode of cancer detection (MoD). Methods Physical activity levels from study baseline (1991–1996) and mammographic information from the time of invasive breast cancer diagnosis (1991–2014) of 1116 women enrolled in the Malmö Diet and Cancer Study cohort were used. Duration and intensity of physical activity were assessed according to metabolic equivalent of task hours (MET-h) per week, or World Health Organization (WHO) guideline recommendations. MBD was dichotomized into low-moderate or high, MA into spiculated or non-spiculated tumors, and MoD into clinical or screening detection. Associations were investigated through logistic regression analyses providing odds ratios (OR) with 95% confidence intervals (CI) in crude and multivariable-adjusted models. Results In total, 32% of participants had high MBD at diagnosis, 37% had non-spiculated MA and 50% had clinical MoD. Overall, no association between physical activity and MBD was found with increasing MET-h/week or when comparing women who exceeded WHO guidelines to those subceeding recommendations (ORadj 1.24, 95% CI 0.78–1.98). Likewise, no differences in MA or MoD were observed across categories of physical activity. Conclusions No associations were observed between pre-diagnostic physical activity and MBD, MA, or MoD at breast cancer diagnosis. While physical activity is an established breast cancer prevention strategy, it does not appear to modify mammographic characteristics or screening detection.

Hydrogen (H2) is a highly efficient and clean energy source with the potential for renewable energy. The production of H2 from biological routes such as biophotolysis, photofermentation, dark fermentation, and bioelectrochemical production is characterized as a renewable alternative to current production, which is mainly based on energy-intensive electrochemical and thermochemical processes and responsible for the emission of high amounts of environmentally harmful compounds. Dark fermentation is the most efficient and cost-effective method for producing biohydrogen, making it a key research focus. This article offers a comprehensive overview of the dark fermentation process with the aim of enhancing hydrogen productivity and yields. Aspects related to the main substrates used, the inoculum sources and their pretreatment, and physical-chemical parameters of the process are covered. Furthermore, this manuscript addresses topics such as process integration, genetic and metabolic engineering of fermentative microorganisms, and the main types of bioreactors aimed at greater yields and productivity of biohydrogen to enable its production through dark fermentation on a larger scale.

This study was conducted to determine if embedding effective study strategies in a course would result in an increased use of these strategies and, therefore, increase success and retention in introductory-level science, technology, engineering, and math (STEM) courses. An interdisciplinary team of STEM faculty members created study strategies video modules that were embedded in their courses. A concurrent course in the same subject was taught without the modules, with this course serving as a control. Data were collected regarding course content knowledge, study strategies awareness, study strategies use, student confidence, course completion, course success, and course retention. Over the course of 3 semesters, faculty team members collected data via pre- and posttests and surveys. Completion, success, and retention data were obtained from college records. A significant change (p < 0.0001) in the use of flashcards, interleaving, spaced practice, and the Pomodoro Technique was seen in students exposed to the study strategies modules. A significant change (p < 0.01) was also seen in time management in the experimental group. Although results indicate that exposure to study strategies makes students aware of their skill deficits, efficacy data indicate that other factors keep them from fully adopting new study techniques.

The United Nations Educational, Scientific, and Cultural Organization (UNESCO) highlights the relevance of using information and communications technology (ICT) in education for improving the quality of education. To achieve this goal, it is necessary to extend research on digital competences in education. To advance the development of digital competencies it is necessary to take account of how teachers perceive these. In addition, systematic reviews of the literature on ICT and education show an imbalance regarding the amount of research from Africa compared to other regions of the world. In this sense, the objective of this study carried out between March 2019 and April 2020 was to analyse the perceptions of primary school teachers from 8 African countries about their digital competences. The teachers were master's students in teacher training on virtual platforms. A mixed methodological perspective (quantitative-qualitative) was adopted and a questionnaire with closed and open-ended questions was applied. The quantitative and qualitative analyses show that the teachers recognised their digital competence at all 3 levels. The needs highlighted by teachers were in developing their knowledge of how to create content with the support of technology. However, the available resources, which differed in the participants' work contexts and did not enable the equal use of ICT in all African countries, was an important issue highlighted by the participants. It is recommended that teacher training in digital competence is prepared using instructional design that promotes innovation and contact with real teaching-learning situations.

Abstract Background Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Results Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10 −/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10 −/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10 −/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10 −/− mice than the distinct microbiota reassembled in non-inflamed WT hosts. Conclusions Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract

Introduction: The time elapsed from diagnosis to hematopoietic stem cell transplantation (HSCT) is influenced by numerous factors. In Brazil, patients using the public health system are also dependent on the availability of HSCT-specific beds in the hematology ward. Objective and Methods: We conducted a cohort study of listed patients who underwent allogeneic HSCT at a Brazilian public hospital to investigate the impact of the waitlist time on post-HSCT survival. Results: The median time from diagnosis to HSCT was 19 months (IQR, 10 - 43), of which 6 months (IQR, 3 - 9) were spent on the waitlist. The time on the waitlist for HSCT appeared to influence mainly the survival of adult patients (≥ 18 years), with an increasing risk according to this time (RR, 3.53 and 95%CI, 1.81 - 6.88 for > 3 and ≤ 6 months; RR 5.86 and 95%CI, 3.26 - 10.53 for > 6 and ≤ 12 months, and; RR 4.24 and 95%CI, 2.32 - 7.75 for > 12 months). Conclusion: Patients who remained on the waitlist for less than 3 months had the highest survival (median survival, 856 days; IQR, 131 - 1607). The risk of reduced survival was about 6-fold higher (95%CI, 2.8 - 11.5) in patients with malignancies.

Background/objectives: Respiratory muscle training (RMT) was recognized as an effective means to improve respiratory muscle (RM) strength and enhance exercise performance. The purpose of this study was to examine the effect of low-intensity RMT on RM strength, pulmonary function, and performance. Methods: Fourteen healthy active adults were assigned randomly to either a training or placebo group. The training group completed six weeks of RMT, which consisted of a first week, 1 set of 15 min/d, 5 d/wk at 10–25% of maximal inspiratory pressure (PImax), and the remaining 5 weeks, 2 sets of 15 min/d, 5 d/wk, at 30% PImax. The placebo group followed the same protocol but with almost no additional ventilatory resistance. Measurement of RM strength and endurance, spirometry, and endurance exercise performance were obtained before and after the RMT program. Results: In the training group, PImax (+14%) and maximal expiratory pressure (PEmax, +27%), forced vital capacity (FVC, +3.6%), maximal oxygen uptake (VO2max, +11%), and time to exhaustion (Tlim90%, +25%) increased significantly from baseline values (P

BACKGROUND: In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results. METHODS: This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [177Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([177Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [177Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [177Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting. FINDINGS: Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [177Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65-75) in the [177Lu]Lu-PSMA-617 group and 72·0 years (66-76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3-13·2) in the [177Lu]Lu-PSMA-617 group and 6·8 months (5·2-8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40-0·62). Time to worsening was delayed in the [177Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45-0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42-0·63), and EQ-5D-5L utility score (0·65, 0·54-0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [177Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [177Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only. INTERPRETATION: [177Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment. FUNDING: Advanced Accelerator Applications (Novartis).

Service-learning (SL) is an active methodology built onto reciprocal learning that combines social responsibility and academic learning. Changes in students' profiles and the evolving interaction between educational institutions and society have encouraged the use of similar participative methodologies in diverse contexts, including higher education. Although the focus of these projects usually centers on student learning, SL experiences enable a holistic construction of knowledge that also affects instructors. This study analyzes instructors' perceptions on developing teaching competences in SL projects and overcoming difficulties. The current research, based on a mixed paradigm, collected answers to a semistructured questionnaire from university instructors (n = 34) in 12 Ibero-American countries with experience in SL. The results show how instructors rate positively their acquisition of teaching competences (socioemotional, organizational, and technical competences) when organizing SL projects; however, they experience a lack of training in this specific methodology.