The conversion of CF3-alkenes to gem-difluoroalkenes using reductive cross-coupling strategy has received much attention in recent years, however, the use of green and readily available reducing salt to mediate these reactions remains to be explored. In this work a concise construction of gem-difluoroalkenes, which requires neither a catalyst nor a metal reducing agent, was established. Rongalite, a safe and inexpensive industrial product, was employed as both a radical initiator and reductant. This procedure was compatible with both linear and cyclic diaryliodonium salts, enabling a wide variety of substrates (>70 examples). The utility of this approach was demonstrated through gram-scale synthesis and efficient late-stage functionalizations of anti-inflammatory drugs.

Organic solar cells (OSCs) have received widespread attention due to light weight, low cost, semitransparency and ease of solution processing. By continuously improving materials design, active layer morphology, and device fabrication techniques, the power conversion efficiency (PCE) of OSCs have exceeded 20%. The morphology of the active layer, which includes the phase separation structure, the degree of crystallinity of molecules, and the domain sizes, plays a critically important role in the performance, which is significantly influenced by the crystallization dynamics of the donor and acceptor. Therefore, it is crucial to comprehensively understand how the dynamics impact the film structure and how to effectively employ the kinetic procedure to enhance the structure of the active layer in OSCs. In this review, the methods and principles of kinetics characterization were introduced. Afterwards, the latest advancements in the control of film-forming and the post annealing process are outlined, unveiling the underlying mechanism. In conclusion, the potential and future of OSCs were anticipated and projected. Researchers may gain a comprehensive comprehension of how the dynamic process affects the morphology through this review, potentially enhancing the performance of OSCs.

Artificial Intelligence-guided mapping of persistent atrial fibrillation:

Aggressive Treatment of Atrial Fibrillation in Hypertrophic Cardiomyopathy

Monoclonal antibodies (MAbs) are powerful therapeutic tools in modern medicine and represent a rapidly expanding multi-billion USD market. While bioprocesses are generally well understood and optimized for MAbs, online quality control remains challenging. Notably, N-glycosylation is a critical quality attribute of MAbs as it affects binding to Fcγ receptors (FcγR), impacting the efficacy and safety of MAbs. Traditional N-glycosylation characterization methods are ill-suited for online monitoring of a bioreactor; in contrast, surface plasmon resonance (SPR) represents a promising avenue, as SPR biosensors can record MAb-FcγR interactions in real-time and without labelling. In this study, we produced five lots of differentially glycosylated Trastuzumab (TZM) and finely characterized their glycosylation profile by HILIC-UPLC chromatography. We then compared the interaction kinetics of these MAb lots with four FcγRs including FcγRIIA and FcγRIIB at 5 oC and 25 oC. When interacting with FcγRIIA/B at low temperature, the differentially glycosylated MAb lots exhibited distinct kinetic behaviours, contrary to room-temperature experiments. Galactosylated TZM (1) and core fucosylated TZM (2) could be discriminated and even quantified using an analytical technique based on the area under the curve (AUC) of the signal recorded during the dissociation phase of a SPR sensorgram describing the interaction with FcγRIIA (1) or FcγRII2B (2). Because of the rapidity of the proposed method (less than 5 minutes per measurement) and the small sample concentration it requires (as low as 30 nM, exact concentration not required), it could be a valuable process analytical technology for MAb glycosylation monitoring.

A document by Mousa Ahmadpour-kacho. Click on the document to view its contents.

The global health workforce crisis, simmering for decades, was brought to a rolling boil by the COVID-19 Pandemic in 2020. With scarce literature, evidence, or best practices to draw from, countries around the world moved to flex their workforces to meet acute challenges of the pandemic, facing demands related to patient volume, patient acuity, and worker vulnerability and absenteeism. One early hypothesis suggested that the acute, short-term pandemic phase would be followed by several waves of resource demands extending over the longer term. However, as the acute phase of the pandemic abated, temporary workforce policies expired and others were repealed with a view of returning to “normal”. The workforce needs of subsequent phases of pandemic effects were largely ignored despite our new equilibrium resting nowhere near our pre-COVID baseline. In this paper, we describe Canada’s early pandemic workforce response. We report the results of an environmental scan of the early workforce strategies adopted in Canada during the first COVID wave of the COVID 19 pandemic. Within a three-part framework for supporting a sustainable health workforce, we describe 470 strategies and policies that aimed to increase the numbers and flexibility of health workers in Canada, and to maximise their continued availability to work. These strategies targeted all types of health workers and roles, enabling changes to the places health work is done, the way in which care is delivered, and the mechanisms by which it is regulated. Telehealth strategies and virtual care were the most prevalent, followed by role expansion, licensure flexibility, mental health supports for workers, and return to practice of retirees. We explore the degree to which these short-term, acute response strategies might be adapted or extended to support the evolving workforce’s long-term needs.

There is a gap between healthcare workforce research and decision-making in policy and practice. This matters more than ever given the urgent staffing crisis, with shortfalls of key workers and increasing service pressures. As a national research network, we held the first ever UK forum on health and care workforce research and evidence in March 2023 which aimed to bridge this gap. We brought together clinical and system leaders, policymakers and regulators with workforce researchers. Fifteen sessions convened by leading experts combined knowledge exchange with deliberative dialogue over two days. Topics ranged from workforce analytics, forecasting, international migration to interprofessional working. In these small groups, important knowledge gaps were identified, where existing research had not reached decision-makers. Managers were not aware of accepted high quality evidence in areas like the relationship between registered nurse staffing levels and patient outcomes. Participants also identified important gaps in research, both topic area and study design. More work is needed to engage new disciplines, from labour economics and occupational health to academic human resources. Mobilising knowledge across disciplines will strengthen the quality and range of research as well as identifying relevant and novel interventions. Discussion at the forum highlighted a number of national and local workforce initiatives which had been implemented at pace, from virtual wards to e-rostering and apprentice levies, without a good evidence base or concurrent evaluation. The pandemic had accelerated many changes, including important shifts in skill mix and new roles with little learning from other countries and systems. Existing evaluations were often small-scale or focused on individual, rather than organisational, solutions in areas such as staff wellbeing. The paper provides a summary of an emerging UK workforce research agenda developed at the forum meeting, together with actions to build workforce research capacity and increase reach of findings into policy and practice.

Patent foramen oval and ESUS in cryptogenic stroke: still a complex puzzleDiana-Elena Iov1,2, MD, Mariana Floria1,3*, MD, PhD, Daniela Maria Tanase1,3, MD, PhD1Faculty of Medicine, Department of Internal Medicine, University of Medicine and Pharmacy ”Grigore T. Popa”, 700111 Iasi, Romania.2Emergency Clinical Hospital ”Saint Spiridon”, Institute of Gastroenterology and Hepatology, 700111 Iasi, Romania.3Emergency Clinical Hospital ”Saint Spiridon”, Internal Medicine Clinic, 700111 Iasi, Romania.Running title: Patent foramen oval related stroke

A document by Ahmed Qasim Mohammed Alhatemi. Click on the document to view its contents.

Time to standardise terminology in the ultrasound study of the pelvic floor of pregnant women Joelene Murdoch-Ward, Irmina Nahon, Sally De-Vitry Smith, Eliza Bernardi, Tamara WoodsUniversity of Canberra, Faculty of Health, Canberra ACT, Australia. The Physiotherapy Clinic, Sydney NSW, AustraliaUniversity of Canberra, Faculty of Health, Canberra ACT, Australia 2610University of Canberra, Faculty of Health, Canberra ACT, Australia 2610The Physiotherapy Clinic, Sydney NSW, AustraliaThe Physiotherapy Clinic, Sydney NSW, Australia

The development of switchable solvent-free multicomponent reactions to build high-value-added products is an important demand for organic synthesis. Herein, we detailed the successful implementation of a switchable strategy for the construction of diverse 4-fluoroalkyl-1,4-dihydropyrimidines and 4-fluoroalkyl-pyrimidines via a solvent/additive-free [3 + 2 + 1] annulation, starting from readily available enamines, trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol and amidines hydrochloride. This reaction conforms to the concept of green synthesis, and provides a new avenue to access valuable fluorinated heterocycles.

The AYA gap for rhabdomyosarcomaSimone Hettmer1 and Lars H. Lindner2Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.Department of Medicine III, LMU University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.To whom correspondence should be addressed. Email: [email protected]. Phone: +49 761 270-45140; Fax: +49 761 270-4518Cancer is the leading cause of death among adolescents and young adults (AYAs). Cancers diagnosed during the AYA period - defined by the National Cancer Institute as the age from 15 to 39 years - account for approximately 5% of all cancers [1]. As per the national report on the status of cancer (study period 2015-2019, [1]), 5-year relative survival rates for both children and AYAs suffering from cancer are high (85.1% for children and 85.8% for AYAs), and improvements in survival over time appear to be similar for both age groups [1]. Yet, the spectrum of cancer types diagnosed in AYAs varies widely. The most common malignancies are female breast cancer (15%), thyroid cancer (15%), testicular cancer (8%) and melanomas (7%) [1], but AYAs may also suffer from so-called pediatric cancers with peak incidence during childhood. When compared to their childhood counterparts, worse outcomes were reported for AYAs diagnosed with pediatric cancers, including but not limited to leukemias [2] and sarcomas [3]. This „AYA gap“ is of concern to both pediatric and adult oncologists.The accompanying paper by Harrison et al examines a cohort of 2151 patients with rhabdomyosarcomas (RMS) enrolled in consecutive Children’s Oncology Group (COG) trials, including 19% AYAs aged 15-39 years and 81% children aged 0-14 years [4]. Compared to children with RMS, AYAs experienced significantly lower 5-year event-free survival (EFS; 44% vs. 67%) and 5-year overall survival (OS; 52% vs. 78%). These observations are in line with a recent retrospective analysis of nearly 2000 patients treated on European paediatric Soft Tissue Sarcoma Group (EpSSG) protocols [3]. Importantly, relative survival of AYAs with RMS treated on EpSSG and COG protocols appears to be better [3, 4] than the survival observed in epidemiological studies such as EUROCARE-5 (39,6% 5-year relative survival among RMS patients aged 15–19 years, and 36·4% for those aged 20–39 years; study period 2000-2007 [5]). Survival benefits for AYA patients treated on pediatric RMS protocols are consistent with previous observations in AYAs receiving treatment according to pediatric acute lymphoblastic leukemia (ALL) protocols [2] or at pediatric cancer centers/ sites with pediatric oncology expertise [6]. AYA cancer patients appear to benefit from chemotherapy dose intensities higher than what is generally prescribed to older patients. They may also draw advantages from pediatric standards with respect to planning of multimodal treatment and cancer staging. For example, the bone marrow (rarely ever involved in adult-type soft tissue sarcomas (STS)) is the most frequent site of metastases in AYAs with RMS treated within the COG cohort reported by Harrison et al [4] and should always be considered when planning pre-treatment examinations of AYAs with RMS. All taken together, adult oncology providers of AYA patients with RMS are well advised to consult their pediatric oncology colleagues and/ or consider referral to an institution with pediatric oncology expertise.AYA cancer patients treated on pediatric protocols – including those suffering from RMS - still experience worse outcomes than their pediatric counterparts [2]. There is ample evidence to support higher risk biology, more aggressive clinical phenotypes and higher rates of early treatment failures in AYAs diagnosed with pediatric cancers – including leukemias andsarcomas- compared to children diagnosed with the same malignancies [2-4]. For RMS tumors, higher rates of alveolar histology tumors and metastatic disease in AYAs were observed in the COG cohort reported here [4], as well as in the EpSSG and other retrospective studies [3, 7]. In addition to higher-risk disease manifestation, more frequent treatment-related toxicities and higher rates of withdrawal from treatment contribute to worse outcomes of AYAs compared to children with cancer [2]. There is a direct association between age and treatment-related deaths for patients undergoing ALL treatment on pediatric protocols [2]. Harrison et al do not comment on differences in treatment-related toxicities between children and AYAs with RMS, but higher rates of vincristine neurotoxicity, nausea and pain were previously reported in older adolescents undergoing RMS treatment on pediatric protocols. Even in the absence of higher-grade toxicities, a high burden of low-grade adverse events can have a major impact on the ability to function in daily life, continue education, maintain employment or participate in social activities. Many AYAs with cancer need to rely more on their parents/ support persons, which threatens their age-appropriate strive for autonomy and may result in them rebelling against treatment recommendations or failing to self- manage complex medication plans [8]. Active involvement of AYAs in the development of a care plan, which considers dignity, normalcy and family/ social relationships may improve compliance and, ultimately, treatment success.RMS is the most common STS in children and adolescents and often referred to as a pediatric cancer. Nevertheless, it occurs at any age, and up to 40% of all cases are diagnosed in adults (including seniors) [9]. The molecular and histological heterogeneity of pediatric RMS was studied intensively in recent years [10]. However, the insights provided by Harrison et al [4] and Ferrrai et al [3] emphasize that the remarkable diversity apparent across the RMS spectrum is multidimensional. Distinct clinical and biological characteristics of RMS diagnosed in different age groups deserve further attention. The two main pediatric RMS subtypes are embryonal and alveolar RMS, whereas pleomorphic RMS and RMS not otherwise specified are predominant in older adults and considered fundamentally different cancers [9]. To obtain a better understanding of RMS diagnosed in AYAs, future study efforts should aim at investigating the full spectrum of the disease and differentially consider the molecular underpinnings and therapeutic requirements of RMS diagnosed at opposite ends of the AYA age range.

Touch is important for many aspects of our daily activities. One of the most important tactile characteristics is its perceived intensity. However, quantifying the intensity of perceived tactile stimulation beyond subjective self-reports remains challenging. Here, we show that pupil responses can objectively index the intensity of tactile stimulation in the absence of overt participant responses. In Experiment 1 (n=32), we stimulated three reportedly differentially sensitive body locations (finger, forearm, calf) with a single tap of a tactor while tracking pupil responses. Tactile stimulation resulted in greater pupil dilation than a baseline without stimulation. Furthermore, pupils dilated more for the more sensitive location (finger) than for the less sensitive locations (forearm, calf). In Experiment 2 (n=20) we extended these findings by manipulating the intensity of the stimulation with three different intensities, here a short vibration, always at the little finger. Again, pupils dilated more when being stimulated at higher intensities as compared to lower intensities. In summary, pupils dilated more for more sensitive parts of the body at constant stimulation intensity and for more intense stimulation at constant location. Taken together, the results show that the intensity of perceived tactile stimulation can be objectively measured with pupil responses – and that such responses are a versatile marker for touch research. Our findings may pave the way for previously impossible objective tests of tactile sensitivity, for example in minimally conscious state patients.

Interoception is mainly related to morpho-functional characteristics of the insula, which shows hypnotizability-related differences in grey matter volume. Interoceptive accuracy (IA, measured by the heartbeat counting task and by HEP, heartbeat evoked cortical potential) is lower in high (highs) than in low hypnotizables (lows). The aim of the present study was to investigate IA in highs, lows, and medium hypnotizables (mediums), who represent most of the population (according to the Stanford Hypnotic Susceptibility Scale (SHSS), Form A), during a session including a simple relaxation (Part 1) and three trials of consecutive open eyes, closed eyes, heartbeat counting and post-counting conditions (Part 2). ECG and EEG were recorded in 14 highs, 14 mediums and 18 lows. HEP were extracted throughout the entire session and IA index was obtained for the heartbeat counting task. In Part 1, significant hypnotizability-related differences were observed in the right central region in both early and late HEP components, with lows showing positive and highs/mediums negative HEP amplitudes. In Part 2, the same group differences were limited to the early HEP component. Moreover, in the left frontal regions, only mediums modified their HEP during the counting task with respect to the open/closed eyes conditions, whereas highs displayed HEP differences between counting and post-counting rest. In conclusion, highs and mediums seem to be more similar than mediums and lows regarding HEP, despite the absence of differences in the counting task. Nonetheless, a negative correlation between SHSS scores and HEP amplitudes was observed in the regions showing group differences.

Hypoxia Inducible Factor (HIF), the main actor in the cell response to hypoxia, represents a potential target in cancer therapy. HIF is involved in many biological processes such as cell proliferation, survival, apoptosis, angiogenesis, iron metabolism and glucose metabolism. This protein regulates the expressions of Lactate Dehydrogenase (LDH) and Pyruvate Dehydrogenase (PDH), both essential for the conversion of pyruvate to be used in aerobic and anaerobic pathways. HIF upregulates LDH, increasing the conversion of pyruvate into lactate which leads to higher secretion of lactic acid by the cell and reduced pH in the microenvironment. HIF indirectly downregulates PDH, decreasing the conversion of pyruvate into Acetyl Coenzyme A which leads to reduced usage of the Tricarboxylic Acid (TCA) cycle in aerobic pathways. Upregulation of HIF may promote the use of anaerobic pathways for energy production even in normal extracellular oxygen conditions. Higher use of glycolysis even in normal oxygen conditions is called the Warburg effect. In this paper, we focus on HIF variations during tumour growth and study, through a mathematical model, its impact on the two metabolic key genes PDH and LDH, to investigate its role in the emergence of the Warburg effect. Mathematical equations describing the enzymes regulation pathways were solved for each cell of the tumour represented in an agent-based model to best capture the spatio-temporal oxygen variations during tumour development caused by cell consumption and reduced diffusion inside the tumour. Simulation results show that reduced HIF degradation in normoxia can induce higher lactic acid production. The emergence of the Warburg effect appears after the first period of hypoxia before oxygen conditions return to a normal level. The results also show that targeting the upregulation of LDH and the downregulation of PDH could be relevant in therapy.

Ovarian cancer is commonly diagnosed in its late stages, and new treatment modalities are needed to improve patient outcomes and survival. We have recently established the synergistic effects of combination tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and procaspase activating compound (PAC-1) therapies in granulosa cell tumours (GCT) of the ovary, a rare form of ovarian cancer, using a mathematical model of the effects of both drugs in a GCT cell line. Here, to understand the mechanisms of combined TRAIL and PAC-1 therapy, study the viability of this treatment strategy, and accelerate preclinical translation, we leveraged our mathematical model in combination with population pharmacokinetics (PopPK) models of both TRAIL and PAC-1 to expand a realistic heterogeneous cohort of virtual patients and optimize treatment schedules. Using this approach, we investigated treatment responses in this virtual cohort and determined optimal therapeutic schedules based on patient-specific pharmacokinetic characteristics. Our results showed that schedules with high initial doses of PAC-1 were required for therapeutic efficacy. Further analysis of individualized regimens revealed two distinct groups of virtual patients within our cohort: one with high PAC-1 elimination, and one with normal PAC-1 elimination. In the high elimination group, high weekly doses of both PAC-1 and TRAIL were necessary for therapeutic efficacy, however virtual patients in this group were predicted to have a worse prognosis when compared to those in the normal elimination group. Thus, PAC-1 pharmacokinetic characteristics, particularly clearance, can be used to identify patients most likely to respond to combined PAC-1 and TRAIL therapy. This work underlines the importance of quantitative approaches in preclinical oncology.

Intro: Long-term treatment with interferon-alfa (IFN) can reduce the disease burden of patients diagnosed with myeloproliferative neoplasms (MPN). Determining individual patient-responses to IFN-therapy may allow for efficient personalized treatment, reducing both drop out and disease burden. Methods: A mathematical model describing hematopoietic stem cells and the immune system is suggested. Considering the bone marrow and the blood allows for modelling disease dynamics both in the absence and presence of treatment. Through comprehensive modelling of the effects of IFN, the model was related to individualized patient-data consisting of longitudinal hematologic and molecular measurements. Treatment responses are modelled on a population-level, allowing for personalized predictions from a single pre-treatment data point. Results: Personalized fits were found to agree well with data. This allowed for a quantitative description of the treatment-response, yielding a mechanistic interpretation of differences between individual patients. Population-level treatment-responses were simulated. Based on pre-treatment data and the actual treatment scheduling, the population-level response was found to predict the treatment-response of particular patients accurately over a five-year period. Conclusion: Mechanism-based modelling of treatment effects demonstrates that hematologic and molecular observables can be predicted on the level of individual patients. Personalized patient-fits suggest that the effect of IFN-treatment can be quantified and interpreted through mathematical modelling, despite variation in hematologic and molecular response for different patients. Modelling suggests that both hematologic and molecular markers must be considered to avoid immediate relapse. Furthermore, personalized model-fits provides quantitative measures of the hematologic and molecular response, determining when treatment-cessation is appropriate. Proof-of-concept population-level modelling of treatment-responses from pre-treatment data successfully predicted clinical measures for a five-year period. This approach could have direct clinical relevance, offering expert guidance for clinical decisions about IFN-treatment of MPN-patients.