Understanding the response of the Western Mediterranean cephalopods to environment and fishing in a context of alleged winners of change.

Increasing impacts of both fisheries and climate change have resulted in shifts in the structure and functioning of marine communities. One recurrent observation is the rise of cephalopods as fish recede. This is generally attributed to the removal of main predators and competitors by fishing, while mechanistic evidence is still lacking. In addition, climate change may influence cephalopods due to their high environmental sensitivity. We aim to unveil the effects of different anthropogenic and environmental drivers at different scales focusing on the cephalopod community of the Western Mediterranean Sea. We investigate several ecological indicators offering a wide range of information about their ecology, and statistically relating them with environmental, biotic and fisheries drivers. Our results highlight non-linear changes of indicators along with spatial differences in their responses. Overall, the environment drivers have greater effects than biotic and local human impacts with contrasting effects of temperature across the geographic gradient. We conclude that cephalopods may be impacted by climate change in the future while not necessary through positive warming influence, which should make us cautious when referring to them as generalized winners of current changes.

Powering prescription: Mitochondria as "Living Drugs" - Definition, clinical applications, and industry advancements.

Mitochondria's role as engines and beacons of metabolism and determinants of cellular health is being redefined through their therapeutic application as "Living Drugs" (LDs). Artificial mitochondrial transfer/transplant (AMT/T), encompassing various techniques to modify, enrich, or restore mitochondria in cells and tissues, is revolutionizing acellular therapies and the future of medicine. This article proposes a necessary definition for LDs within the Advanced Therapeutic Medicinal Products (ATMPs) framework. While recognizing different types of LDs as ATMPs, such as mesenchymal stem cells (MSCs) and chimeric antigen receptor T (CAR T) cells, we focus on mitochondria due to their unique attributes that distinguish them from traditional cell therapies. These attributes include their inherent living nature, diverse sources, industry applicability, validation, customizability for therapeutic needs, and their capability to adapt and respond within recipient cells. We trace the journey from initial breakthroughs in AMT/T to the current state-of-the-art applications by emerging innovative companies, highlighting the need for manufacturing standards to navigate the transition of mitochondrial therapies from concept to clinical practice. By providing a comprehensive overview of the scientific, clinical, and commercial landscape of mitochondria as LDs, this article contributes to the essential dialogue among regulatory agencies, academia, and industry to shape their future in medicine.

Design principles for cyclin K molecular glue degraders.

Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.

Understanding Stakeholder Dissemination Preferences for an Agriculture, Forestry, and Fishing Injury Surveillance System.

Researchers and epidemiologists are working to improve the capture of agriculture, forestry, and fishing (AgFF) injuries in a variety of ways. A critical component of any surveillance system is the dissemination of information. The purpose of this paper is to report on a survey conducted with AgFF injury surveillance stakeholders to understand preferred dissemination strategies. The survey was distributed using REDCap via web link to organizational stakeholders, which included advisory board members, safety trainers, industry managers and workers, and research collaborators. In total, there were 75 respondents (21% response rate). Occupation and industry influenced preference in update methods. Regarding the length and breadth of updates, 63% of respondents prefer reports (one to five pages), followed by 57% desiring a summary (less than one page), while only 24% wanted a detailed analysis. Social media and news preferences were also different among stakeholders. Surveillance data were desired for 1) trend analysis, 2) tailoring activities and solutions for education, training, outreach and interventions and 3) for research purposes such as grant proposals and evaluation. The dissemination of injury surveillance data should be tailored to the intended audience. Greater attention needs to be paid to the ways in which we share our findings.

Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.

Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.

Delay in the residents' choice for General and Digestive Surgery: Analysis of the period 2018-2022.

INTRODUCTION: Every year hundreds of medical residents choose their specialization in various surgical fields. However, these numbers have been poorly analyzed. The objective of this study was to evaluate the selection of General and Digestive Surgery by medical residents and compare these results with the selection of other surgical specialties. METHODS: Cross-sectional observational study. The data from the selection of the medical residents from surgical specialties and the top 10 most demanded specialties between the years 2018 and 2022 were included. An analysis of adjusted ranking numbers based on the number of available positions was also conducted. RESULTS: The number of available positions in General and Digestive Surgery increased by 17.7% during the study period. However, the selection of our specialty has been delayed, with a median ranking number of 2419 (IQR: 1621-3284) in 2018, and 3484 (IQR: 2306-4156) in 2022 (p: .000). These differences remained significant after adjusting for the number of available positions (p: .000). The choice of Urology, Thoracic Surgery, Cardiovascular Surgery, Gastroenterology, and Paediatrics also declined during this period, while Plastic Surgery, Dermatology, Ophthalmology, Anesthesiology, and Endocrinology improved their numbers. CONCLUSION: The choice of General and Digestive Surgery has been delayed according to the data from the MIR selection of 2018-2022. The increase in the number of available positions has not been associated with a proportional increase in demand.

Analysis of recurrence and risk factors in laparoscopic sandwich technique for parastomal hernia repair.

INTRODUCTION: Parastomal hernias are frequent and highly recurrent. The sandwich technique is a combination of the keyhole and Sugarbaker techniques, using a double intraperitoneal mesh. The objective of this study was to assess the outcomes of the sandwich technique, specifically focusing on recurrence rates. MATERIALS AND METHODS: Observational retrospective study conducted in two tertiary referral centers in Catalonia, Spain. All consecutive patients who underwent parastomal hernia repair using the sandwich technique between 1st January 2016 and 31st December 2021 were included. RESULTS: A total of 38 patients underwent the laparoscopic sandwich technique for parastomal hernia repair. The overall recurrence rate was 7.9% (3/38), with a median follow-up of 39 months (IQR: 12.3-56.5). According to the EHS classification for parastomal hernia, there were 47.4% (18/38) type I defects, 10.5% (4/38) type II defects, 28.9% (11/38) type III defects, and 13.2% (5/38) type IV defects. The used mesh was predominantly TiMesh® (76.3%; 29/38), followed by DynaMesh® IPOM (23.7%; 9/38). Patients with recurrence exhibited higher rates of seroma, hematoma, surgical site infection, and one case of early recurrence attributed to mesh retraction. Consequently, postoperative complications emerged as the primary risk factor for hernia recurrence. CONCLUSION: The sandwich technique demonstrated recurrence rates consistent with those reported in the existing literature.

Factors associated with injury among Maine logging workers.

INTRODUCTION: Despite dramatic improvements in safety, logging remains one of the most dangerous industries in the United States. The purpose of this study was to explore longitudinal injury trends among Maine logging workers. METHODS: Loggers participated in seven quarterly surveys, over the course of 18 months. Categorical and free text data related to traumatic and acute injury, musculoskeletal disorders (MSD), and chronic pain were exported from REDCap into SAS 9.4, Excel, and NVivo, for quantitative and qualitative analysis, respectively. Time to injury was modeled using two different approaches: (1) time to the occurrence of first injury modeled by proportional hazard regression and (2) an intensity model for injury frequency. Two research team members also analyzed qualitative data using a content analysis approach. RESULTS: During the study, 204 injuries were reported. Of the 154 participants, 93 (60.4%) reported musculoskeletal pain on at least one survey. The majority of injuries were traumatic, including fractures, sprains, and strains. Lack of health insurance was found to be related to increased risk of first injury [HR = 1.41, 95% CI = 0.97-2.04, p = 0.069]. Variables found to be related to injury intensity at the univariate level were: (1) a lack of health insurance [HR = 1.51, 95% CI = 1.04-2.20, p = 0.030], (2) age [HR for 10-year age increase;= 1.12, 95% CI = 0.99-1.27, p = 0.082], and (3) years employed in logging industry [HR for 10-year increase = 1.12, 95% CI = 0.99-1.26, p = 0.052]. Seeking medical attention for injury was not a priority for this cohort, and narratives revealed a trend for self-assessment. A variety of barriers, including finances, prevented loggers from seeking medical attention. DISCUSSION: We found that loggers still experience serious, and sometimes disabling, injuries associated with their work. It was unsurprising that many injuries were due to slips, trips, and falls, along with contact with logging equipment and trees/logs. The narratives revealed various obstacles preventing loggers from achieving optimal health. Examples included geographic distance from healthcare, lack of time to access care, and entrenched values that prioritized independence and traditional masculinity. Financial considerations were also consistently cited as a primary barrier to adequate care. CONCLUSION: There is a continued need to emphasize occupational health and safety in the logging industry. Implementation of relevant safety programs is key, but it is likely that the benefits of these will not be fully realized until a cultural shift takes place within this industry.

Podcast 3. Lessons learned: managing financial costs and where you can go for more information.

The patient authors with over 48 years of combined real-world experience with chronic myeloid leukemia, and a healthcare professional, use their own personal experiences to describe the factors that may affect the patien-doctor relationship, patient care and outcomes. The authors believe that this podcast series and associated manuscript will aid both patients and healthcare professionals to improve their patient-doctor relationships and communication through diagnosis, treatment decision-making and learning to live with CML (or another disease). In this episode, they discuss managing financial costs and where to find resources and support groups.

The beginning: diagnosis and selecting your doctor.

The patient authors with over 48 years of combined real-world experience with chronic myeloid leukemia, and a healthcare professional, use their own personal experiences to describe the factors that may affect the patient-doctor relationship, patient care and outcomes. The authors believe that this podcast series and associated manuscript will aid both patients and healthcare professionals to improve their patient-doctor relationships and communication through diagnosis, treatment decision-making and learning to live with CML (or another disease). In this episode, they discuss the importance of the patient-doctor relationship, the patient authors' own diagnosis experiences and considerations when selecting a health care team.

Podcast 2. The journey: staying on top of your cancer.

The patient authors with over 48 years of combined real-world experience with chronic myeloid leukemia, and a healthcare professional, use their own personal experiences to describe the factors that may affect the patient-doctor relationship, patient care and outcomes. The authors believe that this podcast series and associated manuscript will aid both patients and healthcare professionals to improve their patient-doctor relationships and communication through diagnosis, treatment decision-making and learning to live with CML (or another disease). In this episode, they discuss communication between a patient and their healthcare team and establishing a treatment protocol.

The natural history of autosomal dominant polycystic kidney disease. A strategy for grouping families and mutations.

Autosomal dominant polycystic kidney disease (ADPKD) is a main cause of end-stage renal disease. Today, knowledge of its genetic basis has made it possible to develop strategies that prevent the transmission of the disease. OBJECTIVES: The objective of the study was to analyze the natural history of ADPKD in the province of Córdoba and to design a database that allows grouping families with different mutations. PATIENTS AND METHODS: All patients (n = 678) diagnosed with ADPKD followed by the Córdoba nephrology service are included. Various clinical variables (age and sex), genetic variables (mutation in PKD1, PKD2) and the need for renal replacement therapy (RRT) were retrospectively analyzed. RESULTS: The prevalence was 61 cases per 100,000 inhabitants. Median renal survival was significantly worse in PKD1 (57.5 years) than in PKD2 (70 years) (log-rank p = 0.000). We have genetically identified 43.8% of the population, detecting PKD1 mutations in 61.2% and PKD2 mutations in 37.4% of cases, respectively. The most frequent mutation, in PKD2 (c.2159del), appeared in 68 patients belonging to 10 different families. The one with the worst renal prognosis was a truncating mutation in PKD1 (c.9893 G > A). These patients required RRT at a median age of 38.7 years. CONCLUSIONS: Renal survival of ADPKD in the province of Córdoba is similar to that described in the literature. We detected PKD2 mutations in 37.4% of cases. This strategy allows us to know the genetic basis of a large proportion of our population while saving resources. This is essential to be able to offer primary prevention of ADPKD through preimplantation genetic diagnosis.

Bladder Capacity in Women With Overactive Bladder Syndrome: A Cross-sectional Study.

OBJECTIVE: To evaluate bladder capacity in women with idiopathic overactive bladder syndrome (OAB) through bladder diary, cystomanometry, and uroflowmetry and assess the concordance of the different measures of bladder capacity. A secondary objective is to describe the relationship between bladder capacity and urinary frequency in OAB patients. METHODS: An observational cross-sectional multicentric study was conducted, including female patients diagnosed with idiopathic OAB. All participants underwent a urodynamic study and completed a 3-day bladder diary (3dBD). Different parameters were used to calculate bladder capacity: maximum cystometric capacity (MCC) assessed at the end of filling cystometry, voided volume (VV) during the uroflowmetry, maximum voided volume (VVmax), and average voided volume (VVmed), both assessed through the 3dBD. Reproducibility analysis was performed to assess the agreement among the different bladder capacity measures. Intraclass correlation coefficient (ICC) and weighted Kappa index were used. Bladder capacity parameters were also assessed in relation to urinary frequency. RESULTS: Bladder capacity measures were diminished in this population, except for VVmax. Poor correlation was found between the different bladder capacity variables (ICC and weighted Kappa index <0.4). Twenty-four-hour frequency and average VV present a weak negative linear relationship (Pearson coefficient -0.344). CONCLUSION: MCC and average VV are reduced in OAB patients. MCC does not correlate well with functional bladder volumes determined by voiding diary in the OAB population.

Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway.

p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway.

Quality, Usability, and Effectiveness of mHealth Apps and the Role of Artificial Intelligence: Current Scenario and Challenges.

The use of artificial intelligence (AI) and big data in medicine has increased in recent years. Indeed, the use of AI in mobile health (mHealth) apps could considerably assist both individuals and health care professionals in the prevention and management of chronic diseases, in a person-centered manner. Nonetheless, there are several challenges that must be overcome to provide high-quality, usable, and effective mHealth apps. Here, we review the rationale and guidelines for the implementation of mHealth apps and the challenges regarding quality, usability, and user engagement and behavior change, with a special focus on the prevention and management of noncommunicable diseases. We suggest that a cocreation-based framework is the best method to address these challenges. Finally, we describe the current and future roles of AI in improving personalized medicine and provide recommendations for developing AI-based mHealth apps. We conclude that the implementation of AI and mHealth apps for routine clinical practice and remote health care will not be feasible until we overcome the main challenges regarding data privacy and security, quality assessment, and the reproducibility and uncertainty of AI results. Moreover, there is a lack of both standardized methods to measure the clinical outcomes of mHealth apps and techniques to encourage user engagement and behavior changes in the long term. We expect that in the near future, these obstacles will be overcome and that the ongoing European project, Watching the risk factors (WARIFA), will provide considerable advances in the implementation of AI-based mHealth apps for disease prevention and health promotion.

The importance of developing open communication and a professional, long-term relationship between patients with chronic myeloid leukemia and their oncologist.

A good patient-doctor relationship and positive communication strongly influence patient quality of life and clinical outcomes. Demonstrating the importance of communication in the patient-doctor relationship are three patient authors who have 48 years of combined real-world experience with chronic myeloid leukemia (CML) in the USA. Using their own personal experiences, these patient authors and a healthcare professional provide suggestions related to improving patient-doctor relationships and communication at each stage of the journey from diagnosis to learning to live with CML. The authors believe these recommendations are applicable to patients with CML and with other diseases, their caregivers and healthcare professionals.