Multiple sclerosis (MS) has a broad range of symptoms and heterogenous trajectory that requires individualised care. To optimise shared decision-making between healthcare professionals (HCPs) and people with MS (PwMS), it is important to understand communication needs from the patient perspective at diagnosis and throughout their care journey. Two multinational online surveys were conducted to explore (1) communication needs around the time of diagnosis, and (2) PwMS empowerment in communicating their specific needs and symptoms. Questionnaires included ten close-ended questions and were shared among 100 PwMS aged 18-50 years in Australia, Spain, the UK and the USA. Anonymised data were analysed by a core panel of HCPs, PwMS and patient advocacy group representatives, and key recommendations were agreed. The majority of respondents were female (65-80%) and from the UK (80-87%). PwMS and caregivers are often overwhelmed and feel 'lost' at the time of diagnosis. Early regular contact is critical for effective delivery of key information and building a trusting relationship. PwMS value a clear explanation of the healthcare team and next steps, but only around a quarter (26%) had HCP roles clearly explained. PwMS are often uncertain if health changes are related to MS and 42% reported not feeling comfortable discussing 'invisible' symptoms such as cognitive, mood and emotional changes. Most respondents (54%) reported that their MS nurse was the person they were most likely to consult. Support services were not routinely offered; only 26% were informed about patient support groups. The most reported benefit of an MS-specific patient group was 'feeling less alone'. Regular HCP contact after diagnosis, peer group support for PwMS and their caregivers, signposting of reliable and accurate online resources and the timely offer of support services, including psychological support, should be routine elements of care from the point of diagnosis. Multiple sclerosis (MS) is a long-lasting illness that affects the brain and spinal cord. In MS, the body’s own defence system attacks a coating around the nerves, which causes damage. This leads to many symptoms. Some are easy to see, like trouble walking or speaking. Others are ‘hidden’, such as feeling very tired, changes in mood, bladder problems or trouble remembering things. These hidden symptoms can impact quality of life, but they are often missed or ignored. The MS in the 21st Century (MS21) group works with people who have MS, doctors, nurses and patient support groups to make care better. To learn more about what people need, MS21 talked to 30 people recently diagnosed with MS in five European countries. They also did two online surveys with 100 people each in Australia, Spain, the UK and the USA. One survey asked about needs at diagnosis. The other asked about helping patients feel comfortable speaking with their care team. Four important needs came up: first, clear communication about what will happen next and who is in the care team; second, helpful information given at the right time, including for families; third, trusted resources like reliable websites and MS nurses; fourth, support services, such as counselling and patient groups to help with feelings of loneliness. Many people wanted more time with their doctors, more discussion about hidden symptoms and regular offers of emotional support. Meeting these needs early could help people manage MS better and feel more confident about their care.
Women, particularly those from widening participation (WP) backgrounds, remain underrepresented in surgical specialties. The educational pipeline is marked by limited exposure to relatable role models, which may discourage these individuals from pursuing surgical careers. Digital learning platforms offer a novel approach to address this gap. In collaboration with the Widening Participation Medics Network (WPMN), a UK-based charity supporting underrepresented medical students and doctors, we delivered a series of five free webinars. Each featured female surgeons-many from WP backgrounds-discussing surgical careers and personal barriers faced. Attendees ranged from pre-medical students to senior clinicians. Post-event surveys (n = 275, 75% response rate) collected both numerical and free-text responses to evaluate impact on understanding, motivation, and representation. The series reached 369 live attendees globally, with 60% identifying as WP and 27% reporting multiple WP characteristics. 73% of attendees agreed that there are many barriers preventing women from widening participation backgrounds entering into a surgical career and thriving as a surgeon. Exposure to WP-focused content of the webinars significantly improved insight into the challenges women face in surgery (Wilcoxon signed-rank test, p < 0.001, r = 0.74). A high proportion (84%) reported increased motivation to pursue surgery after attending the webinars. Presence of female speakers, surgical theme and WP narratives were the most cited reasons for attendance. Many (33%) had never previously attended an educational event featuring WP discussion. Webinars centered on lived experiences and diversity are effective in providing impactful surgical education and inspiration, especially for underrepresented students and doctors. These findings support the integration of inclusive, role model-led virtual teaching in medical education. Further longitudinal studies are needed to evaluate career progression and retention impacts.
Hidradenitis suppurativa (HS), an inflammatory skin disorder characterized by painful nodules and abscesses, has varying prevalence among different races/ethnicities. This study explored the social drivers of health, burden, and impact of HS among different racial and ethnic groups. An online, cross-sectional survey was conducted among adult patients with HS (September 2023-December 2023) in the USA. Patients were recruited through HS Connect (patient advocacy group) and AmeriSpeak (US national sample panel). Descriptive data were collected using patient-reported outcome measures and de novo questions about patients' disease knowledge and perception, healthcare access and utilization, impact on quality of life (QoL), and social impact. All analyses were descriptive and stratified by racial/ethnic groups. The study included 583 patients (mean age, 34.8 years; 95.5% female) representing a range of racial backgrounds: Black or African American (n = 273; 46.8%), white (n = 236; 40.5%), Two or More Races (n = 47; 8.1%), American Indian or Alaska Native (n = 18; 3.1%), Asian (n = 7; 1.2%), and Native Hawaiian and Other Pacific Islander (n = 2; 0.3%). Ethnic representation also varied (Hispanic/Latino = n = 76; 13.0%). Patients of all races and ethnicities reported considerable QoL impact (Dermatology Life Quality Index, EQ-5D-5L), with results for smaller subgroups (n < 10) included for descriptive completeness only and not intended for comparison with other groups. During flaring, most patients used over-the-counter products/medications (54.2%) or nonmedical intervention/home remedy (56.9%) Up to 36.5% of patients reported challenges in procuring food, utilities, medicine/healthcare, phone, clothing, or childcare when needed in the past year. Among those who paid out-of-pocket for their HS treatment, 55.6% reported that it stopped them from visiting a healthcare provider for treatment. The findings indicate a high burden and impact of HS across all races and ethnicities. Patients reported social drivers of health and challenges with healthcare utilization, indicating the need for integrating social workers and care management teams in dermatology practice, which could facilitate improved care of patients with HS. Hidradenitis suppurativa is a painful skin condition that causes lumps and abscesses. It affects people of all races and ethnicities but is more common in Black or African American individuals. This study surveyed 583 adults in the USA to understand how hidradenitis suppurativa affects people from different racial and ethnic backgrounds. Our focus was on how the disease impacts their daily lives, their ability to access healthcare, how often they visit doctors, their quality of life, and their mental and emotional well-being. Most people said that hidradenitis suppurativa lowers their quality of life and makes daily activities harder. During flaring, many used home remedies instead of seeing a doctor. People suffering from hidradenitis suppurativa also reported trouble getting basic needs such as food, medicine, and transportation. These challenges occurred among patients from different racial and ethnic groups; results for very small subgroups (Asian, Native Hawaiian/Other Pacific Islander) are reported descriptively only and should not be interpreted as representative of these groups or compared with other groups. The research underscores the importance of improving awareness and tailoring care for people with hidradenitis suppurativa, particularly those facing barriers to healthcare.
MRI is essential for diagnosing and monitoring neurological diseases. Conventional protocols require multiple sequences to obtain complementary contrasts, increasing scan time, cost, and tolerability. Generating multiple contrasts from a single acquisition may streamline workflow while maintaining clinical utility. To train attention-based convolutional neural networks (ACNNs) to generate clinical-quality Fluid-Attenuated-Inversion-Recovery (FLAIR), Magnetization-Prepared-Rapid-Gradient-Echo (MPRAGE), R2* maps, and derived contrasts from a single Gradient Echo Plural Contrast Imaging (GEPCI) acquisition. Retrospective. 43 MRI scans from individuals with multiple sclerosis (25/18 F/M, 49 ± 11 years-of-age). 3 T MRI, 3D GEPCI, MPRAGE, and FLAIR. Technical quality of AI-generated contrasts was evaluated against directly acquired MRI using structural similarity index (SSIM). Clinical image quality was assessed by physicians. Lesion volumes and counts were obtained using automated segmentation. One-sample one-sided Wilcoxon signed-rank test was used to establish the clinical quality of images. Agreement between native- and AI-derived lesion volume and lesion count measurements was assessed using intraclass correlation coefficients (ICC). Quantitative accuracy for R2* maps was evaluated using normalized root-mean-square error (NRMSE). AI-generated FLAIR and MPRAGE achieved mean SSIM values of 0.923 ± 0.028 and 0.935 ± 0.022, respectively. Generated R2* maps achieved a mean SSIM of 0.996 ± 0.006 and NRMSE of 0.031 ± 0.020. Physicians-assigned mean clinical quality ratings of 4.2 for GEPCI-FLAIR and 4.5 for GEPCI-MPRAGE exceeded the 4.0 clinical standard on a 1-to-5 scale. Lesion volume and count comparisons from automated segmentation showed strong agreement between AI-generated and ground-truth measurements: R2 = 0.988 and R2 = 0.933, ICC = 0.988 and ICC = 0.967, respectively. AI-GEPCI generated multiple clinically relevant MRI contrasts from a single GEPCI acquisition with high similarity to corresponding acquired images, supporting high-quality, intrinsically co-registered multi-contrast brain evaluation. 2. Stage 1. This study developed a new MRI method called AI‐GEPCI that can create many important brain images from a single scan. Normally, people with neurological diseases need several different MRI scans, which take a long time, are costly, and can be hard to tolerate. We trained artificial intelligence (AI) to turn one GEPCI scan into several clinical images (called FLAIR, MPRAGE, and R2*) that doctors routinely use. The AI‐generated images looked very similar to standard MRI images and were rated as high quality by physicians. This approach may allow faster, more comfortable, and more consistent MRI exams for brain diseases.
Pediatric diseases and thus their medications are described as rarely occurring, moderately occurring, and frequently occurring. The purpose of this study is to identify the most frequently prescribed categories of pediatric medications by pediatric specialists in the city of Mosul. 100 medical prescriptions written by pediatric specialists in their private clinics from various locations in the city of Mosul. Upon receiving a prescription from one of these doctors, the research member would copy the prescription and keep it. When 100 prescriptions were collected, each prescription was examined, and the prescribed medications were classified into groups according to their pharmacological effect. The highest frequency of prescribed drug categories by pediatric specialists in Mosul was antibiotics, with a usage rate of 27.77%, followed by gastrointestinal drugs at 22.22%, then analgesics and antipyretics at 18.88%, then antihistamines at 14.44%, followed by vitamins and nutritional supplements at 8.88%, and lastly respiratory system drugs at 7.77%. The results of the current study show that the most prescribed drug class by pediatricians in Mosul city are the antibiotics. Also, the types of antibiotics prescribed differ significantly in all three countries, and this depends on the protocol of treatment in each country. Other classes of drugs in the other studies show some similarity, as in Mosul City and sometimes show significant differences from Mosul City, and this depends on different factors and on different climates.
Delaying healthcare after episodes of violence can allow hidden injuries and trauma in older adults to worsen. It increases the risk of complications, prolonged recovery, and reduced functional independence. Such delays also heighten emotional distress, potentially leading to anxiety, depression, or long-term psychological harm. To investigate associated factors for delayed healthcare-seeking among older adults victims of violence in Brazil, from 2016 to 2022. A cross-sectional analysis was conducted using 154,991 reported cases of violence against individuals aged 60 years and older, extracted from Brazil's national Notifiable Diseases Information System. Delay was defined as notification to health authorities occurring ≥ 24 h after the episode (used as a proxy for delayed healthcare-seeking and system responsiveness). Multivariate logistic and spatial cluster analysis were applied to assess associated factors and regional patterns. Nearly half of the cases involved delayed healthcare-seeking. Increased likelihood of delay was associated with being female, Indigenous, mixed-race, having behavioral or mental disorders, experiencing sexual or psychological violence, episodes involving multiple perpetrators, and those occurring at night or on weekends. In contrast, delays were less likely among individuals with physical or intellectual disabilities, those identifying as bisexual, and cases involving physical violence or self-harm. Spatial analysis revealed significant geographic disparities, with hotspots of delay concentrated in the North and Northeast regions. Delayed access to healthcare among older victims of violence is widespread and shaped by intersecting demographic, psychosocial, and structural vulnerabilities. Strengthening community-based care, improving health system responsiveness, and addressing systemic inequities are essential to ensuring timely support for this at-risk population.
Circadian rhythm disruption (CRD) is a major driver of immune dysregulation; however, whether CRD promotes ischemic stroke (IS) progression through immune imbalance and the underlying molecular mechanisms remain unclear. Transcriptomic data from human IS brain tissues were analyzed to identify CRD associated regulators using machine-learning approaches. A CRD score model was constructed to quantify circadian disruption. Circadian timing-dependent stroke models were established to evaluate diurnal variation in stroke severity and gene rhythmicity in vivo. Single-cell transcriptomic analysis of peripheral blood mononuclear cell -derived scRNA-seq data was performed to characterize CRD-associated immune remodeling. Virtual gene knockdown analysis using the scTenifoldKnk framework, together with experimental validation including microglial gene silencing and T cell co-culture in vitro, as well as adeno-associated virus (AAV)-mediated gene intervention in a transient middle cerebral artery occlusion (tMCAO) model in vivo, were conducted to assess immunoregulatory effects and neurological recovery. We identified seven hub genes associated with CRD in IS patients. Circadian timing significantly influenced stroke severity, with marked differences in infarct volume across Zeitgeber time points. In parallel, coronin 1C (CORO1C) exhibited rhythmic expression in the brain under physiological conditions, which was disrupted following ischemic stroke. High CRD scores were associated with enhanced CD8+ T-cell activation and reduced M0 macrophages, indicating a proinflammatory immune phenotype. Single-cell analysis revealed activation of PD-1/PD-L1 signaling and Th17 polarization within T-cell subsets, consistent with immune overactivation and functional exhaustion. Virtual knockdown analysis highlighted CORO1C as a central regulator linking neuronal and immune transcriptional programs. In microglia, CORO1C knockdown reduced IL-6 and IFN-γ secretion. In vivo, AAV-shCORO1C treatment decreased cerebral CORO1C expression, attenuated CD8+ T-cell infiltration and inflammatory signaling, enhanced Claudin-5 expression, improved neurological function, and promoted post-stroke recovery. This study indicates that CORO1C acts as a pivotal regulator that mediates circadian rhythm disruption-driven immune dysregulation, thereby influencing stroke progression and neurological recovery.
Intensive care unit (ICU) demand is increasing, while healthcare professional shortages and turnover threaten capacity, care quality, and patient safety. This nationwide survey quantified intention to stay (ITS), leave (ITL), or being undecided among ICU professionals in Germany and assessed associated determinants. An anonymous, nationwide, cross-sectional online survey of ICU physicians, registered nurses, and allied health professionals was conducted by the Young German Interdisciplinary Association of Critical Care and Emergency Medicine between December 2024 and February 2025. Primary outcome was ITS in the ICU for at least three years. Determinants were examined using multinomial logistic regression. Of 1524 questionnaires, 1243 were eligible; median ICU experience was 7 years. 51.1% of respondents were physicians, 39.1% registered nurses and 9.8% allied health professionals. Overall, 45.4% reported ITS, 23.2% ITL, and 31.2% were undecided. A 10-point higher job satisfaction was associated with greater ITS versus being undecided (OR 1.34, 95%-CI[1.24-1.45], p < 0.001) and ITL (OR 1.49, 95%-CI[1.37-1.62], p < 0.001). Similarly, higher perceived family-friendliness was associated with greater ITS versus ITL (OR 1.11, 95%-CI[1.02-1.20], p = 0.013). Rotating day-night shift work was associated with higher ITL (OR 0.56, 95%-CI[0.34-0.92], p = 0.021). Association of annual career development dialogues were attenuated after adjustment, consistent with indirect effects via job satisfaction. More than half of ICU professionals were at risk of leaving intensive care within three years. Job satisfaction and family-friendliness emerged as key correlates of retention. Prospective studies are needed to determine whether these aspects are potentially modifiable factors to improve retention.
The opioid epidemic has fueled the rise of opioid use disorder (OUD), which has led to greater use of medication for opioid use disorder (MOUD), including buprenorphine, methadone, and naltrexone. The rise in ambulatory surgical procedures increases the likelihood of encountering a patient on MOUD and presents unique challenges for ambulatory anesthesiologists. Perioperative management of patients with OUD should ensure rapid recovery and effective analgesia, all while minimizing opioid-related complications. An emphasis on multimodal analgesia, enhanced recovery protocols, and close outpatient follow-up with the MOUD prescriber is crucial.
This qualitative single-case study explores the lived experiences of posttraumatic growth (PTG) and posttraumatic depreciation (PTD) in an individual following spinal cord injury (SCI). A narrative analysis approach enabled the collection of multi-layered and rich insights into the lived experiences of Melanie, a doctor who has had a SCI for over 6 years. Melanie's woven narrative showcases the complex interplay between PTG and PTD, with her adjustment to a new way of living being described as 'an ongoing journey'. We highlight Melanie's emergence of PTG as well as the challenges she has faced in the aftermath of her SCI. The findings represented by five themes: Adapting to a new way of living; Recognising what matters; Relationships and the two sides of its coin; The personal nature of spirituality; and Reflections: 'we are a hard population to talk to' demonstrate the coexistence of PTG and PTD in the aftermath of a traumatic event. Future research should explore this further, given the potential implications for the provision of holistic and person-centred SCI rehabilitation strategies.
Medicine, as both clinical and moral practice, is increasingly complex. As such, there is growing appreciation for the importance of practical wisdom (phronesis), a multidimensional capacity that clinicians develop as they navigate practice. Narrative serves as a mode by which clinical exemplars communicate wisdom and therefore provides a rich structure through which practical wisdom can be observed as manifest in lived experience. The purpose of this study was to analyze clinical phronesis narratives to uncover how participants understand practical wisdom through the real-life challenges of clinical encounters. This article describes a qualitative study using structured interviews of 62 participants (40 medical students and 22 physicians). Phronesis narratives describe a particular clinical situation involving an ethically or professionally challenging patient case in which respondents thought practical wisdom was demonstrated. Narratives frequently identified practical wisdom as being needed in encounters involving patient advocacy, individualized patient care, and communication skills. Character traits associated with practical wisdom included empathy, patience, and emotional intelligence. Narratives most often revealed dimensions of practical wisdom such as person-centeredness, poise, or goal-directed decision making. Findings confirm the clinical relevance and multiple dimensions of practical wisdom in medicine "in vivo" that had previously been described theoretically "in vitro." Analysis also revealed that clinical medical students appear able to observe practical wisdom in their supervising physicians, highlighting the need for role-modeling by wise exemplars. The moral content of clinical medicine can be illuminated by rich narratives that can assist in the formation of wise clinicians. Based on the richness of moral content found in these phronesis narratives, the inclusion of narrative-based practices in medical education may help cultivate practical wisdom in medicine.
In both the U.S. and Wisconsin, Black women and infants experience significantly higher rates of morbidity and mortality than their white counterparts. Our research team set out to explore how a community-based and culturally informed perinatal support model could address the needs of Black mothers and their families. We developed and implemented the Today Not Tomorrow Pregnancy and Infant Support Program (TNT-PISP), a community-based, culturally informed perinatal support model integrated with traditional obstetrical care. From October 2019 to August 2022, we held monthly support group sessions facilitated by Black community-based doulas, Black physicians, and community partners. Twenty-five participants engaged in topic-focused and freeform sessions to discuss mental health, breastfeeding, peripartum care, and medical racism. Data were collected through semi-structured interviews and focus groups and analyzed using the Daughtering Method and reflexive thematic analysis. Participants emphasized the importance of shared Black identity and culture in fostering connection and trust. The group's open, judgment-free environment allowed for meaningful conversations and emotional support. Participants valued the exchange of parenting knowledge and community resources. The program's flexible structure and child-friendly setting were key strengths, enabling consistent participation despite busy schedules. This study highlights the potential of community-based, culturally informed perinatal support programs to promote health equity for Black women and infants. Future research should explore such programs' long-term impacts and scalability in diverse settings. Continued efforts to integrate culturally relevant care models into traditional healthcare systems may help promote health inequities in Black communities.
The study aimed to investigate the prevalence of osteoporosis in children and adolescents with transfusion-dependent thalassemia (TDT) and evaluate the diagnostic value of different osteoporosis indicators. Clinical data were collected from children and adolescents with TDT treated with blood transfusion between March 2022 and January 2024 at Huizhou Central People's Hospital and Huizhou First Hospital. The patients were grouped according to the presence of osteoporosis (International Society for Clinical Densitometry [ISCD] criteria). Of 138 patients included in the study, 48 (34.8%) had osteoporosis. The patients with osteoporosis mainly had asymptomatic grade I fractures of the spine. Using the dual-X-ray absorptiometry (DXA) standards from the World Health Organization, height-corrected TBLH Z-score ≤-2 was associated with osteoporosis (30.4% vs. 14.9%, P = 0.035), displaying 30.4% sensitivity and 85.1% specificity. According to the Chinese DXA standards, height-corrected and age-specific Z-scores ≤-2 were not associated with osteoporosis. The prevalence of osteoporosis among children and adolescents with TDT was 34.8%, indicating the need for screening for osteoporosis in that population. In TDT, the diagnosis of osteoporosis requires early detection of spinal fractures because bone density assessed by DXA is of limited value.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally. Ferroptosis, a regulated form of cell death, has emerged as a promising frontier in CRC treatment. The transcriptional regulator ETV4 (ETS variant transcription factor 4) is implicated in CRC pathogenesis. However, its functional role has not been fully elucidated, and its potential to modulate ferroptosis in CRC is entirely unknown. This study aimed to investigate whether ETV4 modulates ferroptosis in CRC by regulating SLC7A11 and to explore the underlying mechanism involved. Bioinformatic analysis was conducted to detect ETV4 expression and to identify pathways regulated by ETV4. Real‑time quantitative PCR (RT‑qPCR) and Western blot assays were used to measure gene expression at the mRNA and protein levels. The biological functions of ETV4 were assessed via CCK‑8, colony formation, wound‑healing, apoptosis analysis, transmission electron microscopy (TEM) and Transwell assays. Key ferroptosis markers-reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential (JC‑1), and ferrous iron (FerroOrange) were examined to determine whether ETV4 knockdown promotes ferroptosis. ETV4 is highly expressed in CRC tissues and cell lines, and its expression level is positively correlated with advanced TNM stages. Silencing ETV4 suppressed CRC cell proliferation, clonogenicity, and migration. Bioinformatic analysis confirmed that ETV4 may suppress the ferroptosis pathway. Functional assays revealed that ETV4 knockdown enhanced ferroptosis in CRC cells. Mechanistically, ETV4 depletion downregulated SLC7A11, whereas SLC7A11 overexpression reversed the ferroptosis phenotype induced by ETV4 knockdown. ETV4 promotes CRC progression by inhibiting ferroptosis through the upregulation of SLC7A11. Therefore, the ETV4/SLC7A11 axis represents a potential therapeutic target for CRC treatment.
Ketamine may alleviate treatment-resistant depression (TRD) primarily through glutamatergic modulation, with downstream dopaminergic activation. Iron plays an important role in monoaminergic metabolism, that is also implicated in the pathophysiology of TRD. Both Quantitative Susceptibility Mapping (QSM) and Effective Transverse Relaxation Rate (R2*) mapping can determine the extent of iron deposition in the brain. Given that abnormal iron accumulation may reflect dopamine dysfunction, we hypothesized that baseline magnetic substances could predict ketamine's antidepressant effects in patients with TRD. We used data from a double-blind, randomized placebo-controlled trial followed by an extended single-arm open-label study to assess the efficacy of repeated intravenous ketamine in Japanese patients with TRD (jRCTs031210124). This study analyzed the data from the participants who underwent QSM and R2* mapping before receiving ketamine in either phase. Multivariable regression analyses were conducted to explore the association between baseline magnetic susceptibility and R2* with change in MADRS total and subdomain scores. This study included 17 patients with TRD (7 women; mean ± standard deviation age, 42.9 ± 10.6 years). Baseline magnetic susceptibility in the right nucleus accumbens negatively correlated with the change in MADRS retardation symptom scores (β = -0.73, p = 0.003). Moreover, baseline R2* in the left amygdala was negatively associated with the change in MADRS vegetative symptom scores (β = -0.71, p = 0.004). Baseline magnetic substances in the right nucleus accumbens and the left amygdala may be biomarkers to predict the effect of repeated ketamine infusions in patients with TRD.
In nature, photosynthesis is driven by solar light and a large proportion of the visible spectrum is absorbed by the light harvesting complexes (LHCs), which then transfer the energy to the reaction center. Inspired by nature, we implemented a light harvesting energy transfer cascade within biomimetic lipid bilayers of liposomes built with DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), using membrane-anchored fluorescein, 2-(3,6-dihydroxy-9H-xanthen-9-yl)-5-dodecanamidobenzoic acid (FlC12) as primary absorber and membrane anchored eosin Y, hexadecyl 2-(2,4,5,7-tetrabromo-3,6-dihydroxy-9H-xanthen-9-yl)benzoate (EYC16), as energy acceptor to sensitize oxygen and generate the reactive oxygen species 1O2. Finally, the model substrate nicotinamide adenine dinucleotide (NADH) is oxidized by 1O2 within the compartmentalizing liposome nanoreactors. It was observed that our metal-free LHC system has only a minor effect on the photooxidation rate of NADH when the nanoreactor membrane is functionalized symmetrically. By contrast, asymmetric membrane functionalization of the liposome nanoreactor membranes leads to acceleration by 16% to 27% when using multi-colored light emitting diodes (LED) or simulated solar light, respectively.
Fifty years ago, Werner Irnich presented the concept of an optimal pacemaker capable of responding appropriately to various cardiac arrhythmias and perceptual disturbances, and intended to be used in 85% of patients. With this concept, Irnich was far ahead of his time. His proposed circuitry for AV block and atrial fibrillation, as well as his suggestions for antitachycardia pacing and interference detection, were visionary. In the field of rate-adaptive pacing, he introduced AV-time control, the first closed-loop system. Werner Irnich represents the close connection between engineers and physicians in the field of cardiac electrotherapy. His theoretical work on the chronaxie rheobase and the electrode surface, confirmed by experimental data, still forms the basis of modern electrical stimulation today. The most extensive data on the interference immunity of electronic implants comes from his laboratory. In addition to his membership in numerous scientific societies, Werner Irnich served as Senior Editor of the international journal Pacing and Clinical Electrophysiology (PACE) from 1978 to 2013. He passed away on December 2, 2023, at the age of 89, leaving behind his wife Hanni, five children, and twelve grandchildren. We will always remember him with gratitude and deep appreciation for his contributions to cardiac electrostimulation.
Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial. The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenström macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenström macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed). BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenström macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68·5 years (IQR 61·0-75·0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3·0 (2·0-5·0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82·5% (95% CI 72·4-90·1), with one (1·3%) patient reaching complete response, eight (10·0%) reaching very good partial response, 49 (61·3%) reaching partial response, and eight (10·0%) reaching minor response. The median study follow-up was 35·0 months (17·7-47·7). The objective response rate was 81·0% (69·1-89·8) for those who received previous covalent BTK inhibitors and 88·2% (63·6-98·5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%). Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed. Eli Lilly and Company.
Electrostatic charging during helicopter flight is well known. In a helicopter search-and-rescue (SAR) service, a winch is often used to access or extract patients. To avoid injury to the personnel who are hoisted, electrostatic discharge between the helicopter and the ground should be transferred through an electrostatic discharge line. Still, rescue paramedics (RPs) and physicians involved in hoist operations are familiar with electrostatic discharge episodes, so-called "static." There is a surprising lack in medical literature that describes the scope of static. We aimed to investigate the experience with electrostatic discharge during hoist operations among the personnel in the Norwegian SAR service. A nationwide, de-identified, web-based cross-sectional survey. All RPs and physicians who work in the SAR service operated by the 330 Squadron in Norway were invited to participate. Of 81 invited, 74 responded (91%). The mean length of experience was 13 years (range, 2-31), and all RPs and 73% of physicians had experienced static. The median number of static experienced was 10 (range, 1-200). Mild static had been experienced by 85%, moderate static by 61%, and severe static by 23%. RPs were both significantly more experienced than physicians and had experienced more static, with a higher degree of severity. Notably, 30% of participants answered that static is a problem for the SAR service, and 24% of participants were worried about potential long-term effects. In this nationwide survey, we found that experience with electrostatic discharge, "static," is common among personnel involved in hoist operations in the Norwegian SAR service. Many participants had experienced a severe degree of static, and 24% of participants were concerned about long-term effects. This survey establishes a need to further assess the scope and implications of static in the SAR service.
Epicardial radiofrequency ablation can fail when lesions are not sufficiently deep or transmural, yet intraoperative feedback remains largely indirect. This study presents a fiber-based, side-viewing near-infrared spectroscopy (NIRS) probe with multiple source-detector separations (SDS) to enable depth-sensitive mapping of lesions on the porcine left-ventricular epicardium. Monte Carlo simulations predicted progressively deeper sampling with increasing SDS, motivating the use of multi-separation acquisition for depth-resolved contrast. Experiments were performed on 11 porcine hearts with 133 irrigated epicardial lesions spanning a wide depth range, with lesion depth ground truth reconstructed from post-stain gross section measurements. SDS-dependent spectral signatures were observed across lesions with depths greater than 4 mm, lesions with depths ≤ 4 mm, adipose tissue, and untreated epicardial muscle, and optical indices capturing these patterns were identified for lesion and adipose classification, as well as for lesion-depth sensitivity. Lesion and adipose indices achieved strong receiver operating characteristic (ROC) performance across SDS (lesion AUC 0.87-0.91; adipose AUC 0.94-0.97), and depth-sensitive indices exhibited monotonic trends with lesion depth (R² up to 0.97). Applying a random forest lesion mask enabled depth-sensitive maps that were consistent with variations in the ground truth.