Inhibition of sodium-glucose cotransporter-2 improves anaemia in mice and humans with sickle cell disease, and reduces infarct size in a murine stroke model.

Sodium-glucose cotransporter-2 (SGLT-2) is expressed in the kidney and may contribute to anaemia and cardiovascular diseases. The effect of SGLT-2 inhibition on anaemia and vascular endpoints in sickle cell disease (SCD) is unknown. A murine model of SCD was studied to determine the effects of the SGLT-2 inhibitor, empagliflozin, on anaemia and stroke size. The University of Michigan's Precision Health Database was used to evaluate the effect of SGLT-2 inhibitors on anaemia in humans with SCD. SCD mice treated with daily empagliflozin for 8 weeks demonstrated increases in haemoglobin, haematocrit, erythrocyte counts, reticulocyte percentage and erythropoietin compared to vehicle-treated mice. Following photochemical-induced thrombosis of the middle cerebral artery, mice treated with empagliflozin demonstrated reduced stroke size compared to vehicle treated mice. In the electronic health records analysis, haemoglobin, haematocrit and erythrocyte counts increased in human SCD subjects treated with an SGLT-2 inhibitor. SGLT-2 inhibitor treatment of humans and mice with SCD is associated with improvement in anaemic parameters. Empagliflozin treatment is also associated with reduced stroke size in SCD mice suggesting SGLT-2 inhibitor treatment may be beneficial with regard to both anaemia and vascular complications in SCD patients.

Does visual or mechanosensory disruption influence risk assessment in coral reef fishes: a preliminary study.

Interpreting and responding to environmental cues from different modalities has survival value. In fish, the role of multimodal perception has been studied in regard to both foraging and risk assessment, with modalities including vision, olfaction, and mechanoreception via lateral lines. We studied reef fish boldness by placing novel objects that obstructed vision, lateral line use, or both into a coral reef environment with native algal samples inside, and then quantifying exploration as a function of obstruction type and as a function of functional diet groups (herbivores, omnivores, carnivores). Fish were more neophobic with more sensory obstructions, displaying longer latencies to visitation across all novel objects. Fish were also less likely to pass by objects that blocked multiple perceptual modalities. Across diets, there is early evidence that different functional groups respond differently to novelty. However, this conclusion requires further study. Overall, our findings provide key insights into perceptual ecology. In turn, this knowledge can be applied to understanding the effects of novel anthropogenic modifications in the marine environment. Such modifications may include positive activities like the construction of substrates to restore coral reefs, coral transplantation to restore reefs, as well as the negative consequences of construction and pollution.

When Fulfilling a Professional Obligation Causes Moral Distress: A New Evaluative Approach.

PURPOSE: The term 'moral distress' was coined by Andrew Jameton to name the anguish that clinicians feel when they cannot pursue what they judge to be right because of institutional constraints. We argue that moral distress in critical care should also be addressed as a function of the constraints of ethics and propose an evaluative approach to the experience considering its implications for professional identity. METHOD: We build on a selective review of the literature and analyze a paradigmatic example of moral distress, namely, clinicians who feel compelled to perform procedures on patients that seem futile. Such cases are commonly cited by clinicians as among the most morally distressing. RESULTS: Our analysis shows that (1) physicians' experiences of moral distress can stem not only from toxic workplace cultures and institutional constraints on their time and resources for patient care but also from the limits of ethical reasoning and (2) an emotion-based evaluative approach to analyzing moral distress is needed to address its hazards for professional identity. CONCLUSION: We propose a new evaluative approach to moral distress with implications for professional identity and the need for institutional education and support.

Neuroma morphology: A macroscopic classification system.

INTRODUCTION/AIMS: Neuromas come in different shapes and sizes; yet the correlation between neuroma morphology and symptomatology is unknown. Therefore, we aim to investigate macroscopic traits of excised human neuromas and assess the validity of a morphological classification system and its potential clinical implications. METHODS: End-neuroma specimens were collected from prospectively enrolled patients undergoing symptomatic neuroma surgery. Protocolized images of the specimens were obtained intraoperatively. Pain data (Numeric rating scale, 0-10) were prospectively collected during preoperative interview, patient demographic and comorbidity factors were collected from chart review. A morphological classification is proposed, and the inter-rater reliability (IRR) was assessed. Distribution of neuroma morphology with patient factors, was described. RESULTS: Forty-five terminal neuroma specimens from 27 patients were included. Residual limb patients comprised 93% of the population, of which 2 were upper (8.0%) and 23 (92.0%) were lower extremity residual limb patients. The proposed morphological classification, consisting of three groups (bulbous, fusiform, atypical), demonstrated a strong IRR (Cohen's kappa = 0.8). Atypical neuromas demonstrated higher preoperative pain, compared with bulbous and fusiform. Atypical morphology was more prevalent in patients with diabetes and peripheral vascular disease. DISCUSSION: A validated morphological classification of neuroma is introduced. These findings may assist surgeons and researchers with better understanding of symptomatic neuroma development and their clinical implications. The potential relationship of neuroma morphology with the vascular and metabolic microenvironment requires further investigation.

Pregabalin-Induced Bullous Pemphigoid: A Case Report of a Rare Drug-Triggered Autoimmune Skin Disorder.

Bullous pemphigoid (BP) is a common autoimmune blistering disorder primarily affecting the elderly, characterized by intense pruritus and tense bullae on the skin. We report the case of a 75-year-old female with a history of breast cancer who developed BP on both feet following the initiation of pregabalin for pain management. Histopathological examination confirmed BP, and symptoms improved with topical corticosteroid treatment and discontinuation of pregabalin. This case highlights the potential of pregabalin to induce BP and underscores the importance of recognizing medication-induced bullous diseases for prompt diagnosis and management.

Mass spectrometry identifies tau C-terminal phosphorylation cluster during neuronal hyperexcitation.

Tau is a microtubule-associated protein implicated in Alzheimer's disease (AD) and other neurodegenerative disorders termed tauopathies. Pathological, aggregated forms of tau form neurofibrillary tangles (NFTs), impairing its ability to stabilize microtubules and promoting neurotoxicity. Indeed, NFTs correlate with neuronal loss and cognitive impairment. Hyperphosphorylation of tau is seen in all tauopathies and mirrors disease progression, suggesting an essential role in pathogenesis. However, hyperphosphorylation remains a generic and ill-defined term, obscuring the functional importance of specific sites in different physiological or pathological settings. Here, we focused on global mapping of tau phosphorylation specifically during conditions of neuronal hyperexcitation. Hyperexcitation is a property of AD and other tauopathies linked to human cognitive deficits and increased risk of developing seizures and epilepsy. Moreover, hyperexcitation promotes extracellular secretion and trans-synaptic propagation of tau. Using unbiased mass spectrometry, we identified a novel phosphorylation signature in the C-terminal domain of tau detectable only during neuronal hyperactivity in primary cultured rat hippocampal neurons. These sites influenced tau localization to dendrites as well as the size of excitatory postsynaptic sites. These results demonstrate novel physiological tau functions at synapses and the utility of comprehensive analysis of tau phosphorylation during specific signaling contexts.

Evaluating the Effectiveness of Laparoscopic Removal of an Accessory Spleen After a Failed Splenectomy for Immune Thrombocytopenia.

Immune thrombocytopenic purpura (ITP) is a challenging condition to manage especially when conventional treatment methods, including splenectomy, fail. This report evaluates the effectiveness of laparoscopic removal of accessory spleen for chronic refractory ITP after an initial splenectomy. A 73-year-old African American male with a history of ITP, previously treated with laparoscopic splenectomy nine years ago, presented with severe thrombocytopenia that was found to be refractory to medical therapies. Platelet counts were monitored, and the absence of Howell-Jolly bodies was noted in the peripheral blood smear. Imaging studies over the past eight years indicated the growth of a mass in the left upper abdomen, suggesting a possible accessory spleen. Given the overwhelming evidence of a splenule in refractory thrombocytopenia, laparoscopic exploration and mass removal were conducted. Histologic analysis of the removed mass confirmed a splenule. Despite the complete removal of the mass, postoperative platelet counts remained consistently low and unresponsive to the resumption of medical therapies. This study emphasizes the limitations of accessory splenectomy for refractory ITP and highlights the need for further research to clarify the long-term effectiveness of this surgical procedure in these patients.

Excited-state symmetry breaking is an ultrasensitive tool for probing microscopic electric fields.

Microscopic electric fields are increasingly found to play a pivotal role in catalysis of enzymatic and chemical reactions. Currently, the vibrational Stark effect is the main experimental method used to measure them. Here, we demonstrate how excited-state symmetry breaking can serve as a much more sensitive tool to assess these fields. Using transient infrared spectroscopy on a quadrupolar probe equipped with nitrile groups we demonstrate both its superior sensitivity and that it does not suffer from the notorious hydrogen-bond induced upshift of the C[triple bond, length as m-dash]N stretch frequency. In combination with conventional ground-state infrared absorption, excited-state symmetry breaking can be used to disentangle even weak specific hydrogen bond interactions from general field effects. We showcase this capability with the example of weak C-H hydrogen bonds in polar aprotic solvents. Additionally, we reveal for the first time symmetry breaking driven not by solvent but by the entropy of the pendant side chains of the chromophore. Our findings not only enhance our understanding of symmetry-breaking charge-transfer phenomena but pave the way toward using them in electric field sensing modality.

Calyceal Rupture Secondary to Nephrolithiasis: A Case Report Emphasizing Early Diagnosis and Management.

Calyceal rupture, defined as the extravasation of urine from the renal calyces into the perinephric or paranephric spaces, typically results from increased intrapelvic pressure due to urinary tract obstruction. This condition can lead to the formation of a perinephric urinoma and severe complications, such as infection, abscess formation, and impaired renal function. Timely diagnosis and management are crucial to prevent these adverse outcomes. Calyceal rupture often results from urolithiasis, with other causes including strictures, tumors, and congenital abnormalities. The rupture occurs when intrapelvic pressure exceeds the tensile strength of the calyceal walls, leading to urine leakage and potential inflammation or sepsis. Calyceal ruptures are quite rare, with their exact incidence not well-documented due to the infrequency of the condition and potential underreporting. Although relatively uncommon, the condition is more prevalent in individuals with recurrent nephrolithiasis and other predisposing factors. Timely recognition and intervention, guided by imaging studies such as non-contrast CT scans, are essential. Conservative management with medical therapy is effective in many cases, but surgical intervention may be necessary for larger stones or complications. This report presents the case of a 36-year-old female with calyceal rupture secondary to nephrolithiasis, presenting with severe flank pain. Upon initial presentation, the patient underwent a thorough workup, including imaging studies, appropriate medical management, and continuous monitoring. She was stabilized, her pain was effectively managed, and she was discharged with a scheduled outpatient follow-up. This case highlights the importance of early diagnosis, comprehensive management, and vigilant monitoring in preventing complications and promoting favorable outcomes.

Fruquintinib-Induced Cerebellar Hemorrhage in Left-Sided Descending Metastatic Colorectal Adenocarcinoma: A Case Report and Risk Assessment.

Colorectal adenocarcinoma is the most prevalent form of colorectal cancer, representing the majority of cases in the United States. The disease is driven by a series of genetic mutations, including alterations in the adenomatous polyposis coli (APC), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS), human epidermal growth factor receptor 2 immunohistochemistry 3+ (HER-2 IHC3+), checkpoint kinase 2 (CHEK-2) and tumor protein P53 (TP53) genes, which lead to malignant transformation. While the standard treatment for metastatic colorectal cancer (mCRC) typically involves chemotherapy and targeted therapies, many patients experience disease progression, necessitating the exploration of novel treatments. Fruquintinib, a highly selective vascular endothelial growth factor (VEGFR) inhibitor, has emerged as a promising option for mCRC patients who have exhausted conventional therapies. However, its use is associated with significant bleeding risks, including rare but severe complications such as cerebellar hemorrhage. This case report presents a patient with mCRC who developed a cerebellar hemorrhage shortly after initiating fruquintinib therapy, highlighting the need for careful patient monitoring and individualized risk assessment to mitigate such serious adverse events.

Immunosuppressant therapy averts rejection of allogeneic FKBP1A-disrupted CAR-T cells.

Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells. In turn, genetic knockout (KO) of FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted by both drugs, was necessary to confer CD19-specific CAR-T cells (19CAR) robust functional resistance to these immunosuppressants. FKBP1AKO 19CAR-T cells maintained potent in vitro functional profiles and controlled in vivo tumor progression similarly to untreated 19CAR-T cells. Moreover, immunosuppressant treatment averted in vivo allorejection permitting FKBP1AKO 19CAR-T cell-driven B cell aplasia. Thus, we demonstrate that genome engineering enables immunosuppressant treatment to improve the therapeutic potential of universal donor-derived CAR-T cells.

Cardiac Surgical Bleeding, Transfusion and Quality Metrics: Joint Consensus Statement by the Enhanced Recovery After Surgery Cardiac Society and Society for the Advancement of Patient Blood Management.

BACKGROUND: Excessive perioperative bleeding is associated with major complications in cardiac surgery, resulting in increased morbidity, mortality and cost. METHODS: An international expert panel was convened to develop consensus statements on the control of bleeding and management of transfusion, and to suggest key quality metrics for cardiac surgical bleeding. The panel reviewed relevant literature from the previous 10 years and used a modified RAND Delphi methodology to achieve consensus. RESULTS: Thirty consensus statements in 8 categories were developed, including prioritizing control of bleeding, pre-chest closure checklists and the need for additional quality indicators beyond re-exploration rate, such as time to re-exploration. Consensus was also reached on the need for a universal definition of excessive bleeding, the use of antifibrinolytics, optimal cessation of antithrombotic agents, and preoperative risk scoring based on patient and procedural factors to identify those at greatest risk of excessive bleeding. Furthermore, there is a need for an objective bleeding scale based on the volume and rapidity of blood loss accompanied by viscoelastic management algorithms and standardized, patient-centered blood management strategies reflecting an interdisciplinary approach to quality improvement. CONCLUSIONS: Prioritizing the timely control and management of bleeding is essential to improving patient outcomes in cardiac surgery. To this end, a cardiac surgical bleeding quality metric that is more comprehensive than re-exploration rate alone is needed. Similarly, interdisciplinary quality initiatives that seek to implement enhanced quality indicators will likely lead to improved patient care and outcomes.

Neuroma-to-Nerve Ratio: Does Size Matter?

BACKGROUND AND OBJECTIVES: Anatomic features of neuromas have been explored in imaging studies. However, there has been limited research into these features using resected, ex vivo human neuroma specimens. The aim of this study was to investigate the influence that time may have on neuroma growth and size, and the clinical significance of these parameters. METHODS: Patients who underwent neuroma excision between 2022 through 2023 were prospectively included in this study. Neuroma specimens were obtained after operative resection. Standardized neuroma size measurements, expressed as a neuroma-to-nerve ratio (NNR), were conducted with ImageJ software. Pain data (numeric rating scale, 0-10) were prospectively recorded during preoperative evaluation, and patient factors were collected from chart reviews. RESULTS: Fifty terminal neuroma specimens from 31 patients were included, with 94.0% of the neuromas obtained from individuals with amputations. Most neuromas were excised from the lower extremities (n = 44, 88.0%). The neuromas had a median NNR of 2.45, and the median injury to neuroma excision interval was 6.3 years. Larger NNRs were associated with a longer injury to neuroma excision interval and with a smaller native nerve diameter. In addition, sensory nerves were associated with a larger NNR compared with mixed nerves. NNR was not associated with preoperative pain or with anatomical nerve distribution. CONCLUSION: This study suggests that neuromas seem to continue to grow over time and that smaller nerves may form relatively larger neuromas. In addition, sensory nerves develop relatively larger neuromas compared with mixed nerves. Neuroma size does not appear to correlate with pain severity. These findings may stimulate future research efforts and contribute to a better understanding of symptomatic neuroma development.

Ketamine - An Imperfect Wonder Drug?

Ketamine is a potent sedative and dissociative anesthetic agent that has been used clinically for over 50 years since it was first developed in the 1960 s as an alternative to phencyclidine (PCP). When compared to PCP, ketamine exhibited a much lower incidence of severe side effects, including hallucinations, leading to its increased popularity in clinical practice. Ketamine was initially used as an anesthetic agent, especially in emergency medicine and in surgical procedures where rapid induction and recovery was necessary. However, over the last few decades, ketamine was found to have additional clinically useful properties making it effective in the treatment of a variety of other conditions. Presently, ketamine has a wide range of clinical uses beyond anesthesia including management of acute and chronic pain, as well as treatment of psychiatric disorders such as major depression. In addition to various clinical uses, ketamine is also recognized as a common drug of abuse sought for its hallucinogenic and sedative effects. This review focuses on exploring the different clinical and non-clinical uses of ketamine and its overall impact on patient care.

Concepts and applications of digital twins in healthcare and medicine.

The digital twin (DT) is a concept widely used in industry to create digital replicas of physical objects or systems. The dynamic, bi-directional link between the physical entity and its digital counterpart enables a real-time update of the digital entity. It can predict perturbations related to the physical object's function. The obvious applications of DTs in healthcare and medicine are extremely attractive prospects that have the potential to revolutionize patient diagnosis and treatment. However, challenges including technical obstacles, biological heterogeneity, and ethical considerations make it difficult to achieve the desired goal. Advances in multi-modal deep learning methods, embodied AI agents, and the metaverse may mitigate some difficulties. Here, we discuss the basic concepts underlying DTs, the requirements for implementing DTs in medicine, and their current and potential healthcare uses. We also provide our perspective on five hallmarks for a healthcare DT system to advance research in this field.

Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer's disease continuum.

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

Challenges and Approaches to Establishing Multi-Pathogen Serosurveillance: Findings from the 2023 Serosurveillance Summit.

Multiplex-based serological surveillance is a valuable but underutilized tool to understand gaps in population-level exposure, susceptibility, and immunity to infectious diseases. Assays for which blood samples can be tested for antibodies against several pathogens simultaneously, such as multiplex bead immunoassays, can more efficiently integrate public health surveillance in low- and middle-income countries. On March 7-8, 2023 a group of experts representing research institutions, multilateral organizations, private industry, and country partners met to discuss experiences, identify challenges and solutions, and create a community of practice for integrated, multi-pathogen serosurveillance using multiplex bead assay technologies. Participants were divided into six working groups: 1) supply chain; 2) laboratory assays; 3) seroepidemiology; 4) data analytics; 5) sustainable implementation; and 6) use case scenarios. These working groups discussed experiences, challenges, solutions, and research needs to facilitate integrated, multi-pathogen serosurveillance for public health. Several solutions were proposed to address challenges that cut across working groups.

Identification, mapping, and self-reported practice patterns of village doctors in Sitakunda subdistrict, Bangladesh.

Background: Informally trained health care providers, such as village doctors in Bangladesh, are crucial in providing health care services to the rural poor in low- and middle-income countries. Despite being one of the primary vendors of antibiotics in rural Bangladesh, village doctors often have limited knowledge about appropriate antibiotic use, leading to varied and potentially inappropriate dispensing and treatment practices. In this study, we aimed to identify, map, and survey village doctors in the Sitakunda subdistrict of Bangladesh to understand their distribution, practice characteristics, clinical behaviours, access to technologies, and use of these technologies for clinical decision-making. Methods: Using a 'snowball' sampling method, we identified and mapped 411 village doctors, with 371 agreeing to complete a structured survey. Results: The median distance between a residential household and the closest village doctor practice was 0.37 km, and over half of the practices (51.2%) were within 100 m of the major highway. Village doctors were predominately male (98.7%), with a median age of 39. After completing village doctor training, 39.4% had completed an internship, with a median of 15 years of practice experience. Village doctors reported seeing a median of 84 patients per week, including a median of five paediatric diarrhoea cases per week. They stocked a range of antibiotics, with ciprofloxacin and metronidazole being the most prescribed for diarrhoea. Most had access to phones with an internet connection and used online resources for clinical decision-making and guidance. Conclusions: The findings provide insights into the characteristics and practices of village doctors and point to the potential for internet and phone-based interventions to improve patient care and reduce inappropriate antibiotic use in this health care provider group.

Different strategies for landing from different heights among people with chronic ankle instability.

BACKGROUND: Lateral ankle sprain (LAS) usually occurs during landing from heights among people with chronic ankle instability (CAI). Although the kinematics when landing on the flat surface has been reported, no studies have explored the effect of different heights on the landing strategies using a trapdoor device among people with CAI. RESEARCH QUESTION: Do people with CAI adopt different landing strategies when drop-landing on the trapdoor device from three heights? METHODS: Thirty-one participants with CAI (24 males and 7 females, age=21.1±1.8 years, height=176.9±7.4 cm, body mass=71.9±9.2 kg, injured side=18 R&13 L) were recruited. They dropped from three different heights (low height (16 cm), medium height (23 cm), high height (30 cm)) with their affected foot landing on a movable surface of a trapdoor device, which was tilted 24° inward and 15° forward to simulate LAS. Kinematic data was collected using a twelve-camera motion capture system. One-way analysis of variance with repeated measures was used to compare the differences between the three heights. RESULTS: Significant height effects were detected in the peak ankle inversion angle (p=0.009, η2p=0.280) and angular velocity (p<0.001, η2p=0.444), and the peak ankle plantarflexion (p=0.002, η2p=0.360), knee flexion (p<0.001, η2p=0.555), and hip flexion (p=0.030, η2p=0.215) angles at the time of peak ankle inversion. Post-hoc tests showed that all the angles and velocities were higher at a low height than at medium (p: 0.001-0.045, d: 0.14-0.44) and high heights (p: 0.001-0.023, d: 0.28-0.66), except for the ankle plantarflexion angle, which was lower at a low height than at medium (p<0.001, d=0.44) and high (p=0.021, d=0.38) heights. SIGNIFICANCE: People with CAI adopt a protective strategy during drop-landing at medium and high heights compared to a low height. This strategy involves increased ankle dorsiflexion angle as well as knee and hip flexion angles.