Real-world effectiveness of sodium-glucose cotransporter-2 inhibitors on the progression of chronic kidney disease in patients without diabetes, with and without albuminuria.

AIM: To examine the renal effects of sodium-glucose cotransporter-2 (SGLT2) inhibition among non-diabetic individuals with chronic kidney disease (CKD) in a real-world setting. METHODS: We collected de-identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73 m2, who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow-up slope was calculated from all evaluations during 90-900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow-up annual slopes. RESULTS: Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin-angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m2. The mean body mass index was 29.1 ± 5.4 kg/m2. During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a UACR >300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was -5.6 ± 7.7 mL/min/1.73 m2 per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m2 per year after SGLT2 inhibitor administration (p <0.001). This effect was independent of UACR. CONCLUSION: In a real-world study of primarily older non-diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.

Grief over patients, compassion fatigue, and the role of social acknowledgment among psycho-oncologists.

OBJECTIVE: Compassion fatigue-that is, secondary traumatic stress (STS) and burnout-is a traumatic emotional state experienced by health care providers and expressed in a reduced capacity to be interested in and empathic to the suffering of others. Compassion fatigue may be related to grief over patients' loss. We examined the relation between grief and compassion fatigue among psycho-oncologists while exploring the impact of social acknowledgment on this association. We hypothesized that social acknowledgment would moderate the relation between grief and compassion fatigue. METHODS: Participants were 60 Israeli psycho-oncologists in a cross-sectional study. Measures consisted of a demographic questionnaire, the Texas Revised Inventory of Grief-Present, the Social Acknowledgment questionnaire, and the Professional Quality of Life Questionnaire. RESULTS: The participants reported relatively high levels of grief and high levels of compassion fatigue. Grief and compassion fatigue were significantly positively associated (STS: r = 0.41, p < 0.01; Burnout: r = 0.45, p < 0.01). A k-means cluster analysis based on social acknowledgment and grief yielded three meaningful clusters: High Grief-Low Social Acknowledgment; Medium Grief-High Social Acknowledgment; and Low Grief-Medium Social Acknowledgment. Levels of STS in the first cluster were significantly higher in comparison to levels of STS in each of the other clusters (F = 6.22, p < 0.01). CONCLUSIONS: Psycho-oncologists experience patient loss as part of their daily work. In response, they may develop grief reactions. This grief, when it is not perceived by them as being socially acknowledged, may result in high levels of STS: a phenomenon with undesirable personal and professional implications.

Compassion fatigue among oncologists: the role of grief, sense of failure, and exposure to suffering and death.

PURPOSE: Oncologists cope with unique work characteristics that increase their risk of developing compassion fatigue-that is, burnout and secondary traumatic stress-and can result in reduced capacity and interest in being empathetic to the suffering of others (Stamm B. The concise ProQOL manual, 2010). At the same time, oncologists can experience compassion satisfaction-that is, the positive aspects of caring. This study explored the associations of compassion fatigue and compassion satisfaction with oncologists' grief and sense of failure beyond their reported exposure to suffering and death. METHODS: Seventy-four oncologists completed self-administered questionnaires examining compassion fatigue, compassion satisfaction, grief, exposure to suffering and death, and sense of failure. RESULTS: The oncologists reported that they face the loss of approximately 50% of their patients, and that their patients suffer from profound emotional and physical pain. High levels of compassion fatigue and grief, and moderate levels of sense of failure, were reported. Findings showed a lack of association between exposure to suffering and death and compassion fatigue and satisfaction. However, grief and sense of failure were found to predict both aspects of compassion fatigue: secondary traumatic stress (p < 0.001, p < 0.003, respectively) and burnout (p < 0.002, p < 0.025, respectively). CONCLUSIONS: These results highlight the importance of the oncologists' subjective experiences of grief and sense of failure, beyond their reports of exposure to suffering and death, in terms of their levels of compassion fatigue. Implications of these findings include the need to develop interventions for oncologists that will allow them to acknowledge, process, and overcome negative experiences of failure and grief.

Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice.

OBJECTIVE: Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE). METHODS: To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)ß. RESULTS: Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNß, and increased survival following SE. SIGNIFICANCE: This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.

Bioadhesive microneedle patches for tissue sealing.

Sealing of soft tissues prevents leakage of gas and liquid, closes wounds, and promotes healing and is, therefore, of great significance in the clinical and medical fields. Although various formulations have been developed for reliable sealing of soft tissue, tradeoffs between adhesive properties, degradation profile, and tissue toxicity limit their clinical use. Hydrogel-based adhesives, for example, are highly biocompatible but adhere very weakly to the tissue and degrade quickly, while oxidized cellulose patches are poorly absorbed and may cause healing complications postoperatively. Here, we present a novel strategy for tissue sealing based on bioadhesive microneedle patches that can spontaneously adhere to tissue surface through electrostatic interactions and swell within it. A series of microneedle patches made of pullulan, chitosan, Carbopol, poly (lactic-co-glycolic acid), and a Carbopol/chitosan combination were fabricated and characterized for their use in tissue sealing. The effect of microneedle composition on the fabrication process, physical and mechanical properties, in vitro cytotoxicity, and in vivo biocompatibility were examined. The needle structure enables microneedles to strongly fix onto various tissues via physical interlocking, while their adhesive properties improve staying time and sealing capabilities. The microneedle patch comprising Carbopol needles and chitosan as a second pedestal layer presented the best results in terms of sealing and adhesion, a consequence of the needle's swelling and adhesion features combined with the supportive chitosan base layer. Finally, single Carbopol/chitosan patches stopped intense liver bleeding in a rat model significantly quicker and with less blood loss compared with commercial oxidized cellulose patches. These microneedles can be considered a promising cost-effective platform for adhering and sealing tissues as they can be applied quickly and painlessly, and require less trained medical staff and equipment.

Design and Evaluation of Dissolvable Microneedles for Treating Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused predominantly by immune dysregulation. The global impact of AD continues to increase, making it not only a significant public health issue but also a risk factor for progression into other allergic phenotype disorders. Treatment of moderate-to-severe symptomatic AD involves general skin care, restoration of the skin barrier function, and local anti-inflammatory drug combinations, and may also require systemic therapy, which is often associated with severe adverse effects and is occasionally unsuitable for long-term use. The main objective of this study was to develop a new delivery system for AD treatment based on dissolvable microneedles containing dexamethasone incorporated in a dissolvable polyvinyl alcohol/polyvinylpyrrolidone matrix. SEM imaging of the microneedles showed well-structured arrays comprising pyramidal needles, fast drug release in vitro in Franz diffusion cells, an appropriate mechanical strength recorded with a texture analyzer, and low cytotoxicity. Significant clinical improvements, including in the dermatitis score, spleen weights, and clinical scores, were observed in an AD in vivo model using BALB/c nude mice. Taken together, our results support the hypothesis that microneedle devices loaded with dexamethasone have great potential as a treatment for AD and possibly for other skin conditions as well.

Evaluation and Optimization of Methods for Generating High-Resolution Retinotopic Maps Using Visual Cortex Voltage-Sensitive Dye Imaging.

The localization and measurement of neuronal activity magnitude at high spatial and temporal resolution are essential for mapping and better understanding neuronal systems and mechanisms. One such example is the generation of retinotopic maps, which correlates localized retinal stimulation with the corresponding specific visual cortex responses. Here we evaluated and compared seven different methods for extracting and localizing cortical responses from voltage-sensitive dye imaging recordings, elicited by visual stimuli projected directly on the rat retina by a customized projection system. The performance of these methods was evaluated both qualitatively and quantitatively by means of two cluster separation metrics, namely, the (adjusted) Silhouette Index (SI) and the (adjusted) Davies-Bouldin Index (DBI). These metrics were validated using simulated data, which showed that Temporally Structured Component Analysis (TSCA) outperformed all other analysis methods for localizing cortical responses and generating high-resolution retinotopic maps. The analysis methods, as well as the use of cluster separation metrics proposed here, can facilitate future research aiming to localize specific activity at high resolution in the visual cortex or other brain areas.

Bacillus subtilis in PVA Microparticles for Treating Open Wounds.

Open wound dressings should provide a moist environment, protect the wound from bacterial contamination, and shield it from further damage. These requirements, however, are hard to accomplish since such wounds are colonized by pathogenic bacteria, including resistant species such as methicillin-resistant Staphylococcus aureus (MRSA). A new approach for treating open wounds that is based on sticky and dissolvable polyvinyl alcohol (PVA) microparticles containing live Bacillus subtilis (B. subtilis) is described. Microparticles, fabricated by the spray-drying technique, were administered directly to an open wound while B. subtilis continuously produced and secreted antimicrobial molecules. B. subtilis in PVA microparticles demonstrated remarkable antibacterial activity against MRSA and S. aureus. In in vivo experiments, both B. subtilis and empty PVA microparticles were effective in decreasing healing time; however, B. subtilis microparticles were more effective during the first week. There was no evidence of skin irritation, infection, or other adverse effects during the 15 day postoperative observation period. This concept of combining live secreting bacteria within a supportive delivery system shows great promise as a therapeutic agent for open wounds and other infectious skin disorders.

Liquid Copolymers as Biodegradable Surgical Sealant.

Surgical sealants are widely used to prevent seepage of fluids and liquids, promote hemostasis, and close incisions. Despite the remarkable progress the field of biomaterials has undergone, the clinical uses of surgical sealants are limited because of their short persistence time in vivo, toxicity, and high production costs. Here, the development of two complementary neat (solvent-free) prepolymers, PEG4 -PLGA-NHS and PEG4 -NH2 , that harden upon mixing to yield an elastic biodegradable sealant is presented. The mechanical and rheological properties and cross-linking rate can be controlled by varying the ratio between the two prepolymers. The tested sealants show a longer persistence time compared with fibrin glue, minimal cytotoxicity in vitro, and excellent biocompatibility in vivo. The neat, multiarmed approach demonstrated here improves the mechanical and biocompatibility properties and provides a promising tissue sealant solution for wound closure in future surgical procedures.

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics.

Over the past years, advanced in vitro pulmonary platforms have witnessed exciting developments that are pushing beyond traditional preclinical cell culture methods. Here, we discuss ongoing efforts in bridging the gap between in vivo and in vitro interfaces and identify some of the bioengineering challenges that lie ahead in delivering new generations of human-relevant in vitro pulmonary platforms. Notably, in vitro strategies using foremost lung-on-chips and biocompatible "soft" membranes have focused on platforms that emphasize phenotypical endpoints recapitulating key physiological and cellular functions. We review some of the most recent in vitro studies underlining seminal therapeutic screens and translational applications and open our discussion to promising avenues of pulmonary therapeutic exploration focusing on liposomes. Undeniably, there still remains a recognized trade-off between the physiological and biological complexity of these in vitro lung models and their ability to deliver assays with throughput capabilities. The upcoming years are thus anticipated to see further developments in broadening the applicability of such in vitro systems and accelerating therapeutic exploration for drug discovery and translational medicine in treating respiratory disorders.

Extrinsic Factors Shaping the Skin Microbiome.

Human skin, our most environmentally exposed organ, is colonized by a vast array of microorganisms constituting its microbiome. These bacterial communities are crucial for the fulfillment of human physiological functions such as immune system modulation and epidermal development and differentiation. The structure of the human skin microbiome is established during the early life stages, starting even before birth, and continues to be modulated throughout the entire life cycle, by multiple host-related and environmental factors. This review focuses on extrinsic factors, ranging from cosmetics to the environment and antibacterial agents, as forces that impact the human skin microbiome and well-being. Assessing the impact of these factors on the skin microbiome will help elucidate the forces that shape the microbial populations we coexist with. Furthermore, we will gain additional insight into their tendency to stimulate a healthy environment or to increase the propensity for skin disorder development.

High-resolution VSDI retinotopic mapping via a DLP-based projection system.

High-resolution recording of visual cortex activity is an important tool for vision research. Using a customized digital mirror device (DMD) - based system equipped with retinal imaging, we projected visual stimuli directly on the rat retina and recorded cortical responses by voltage-sensitive dye imaging. We obtained robust cortical responses and generated high-resolution retinotopic maps at an unprecedented retinal resolution of 4.6 degrees in the field of view, while further distinguishing between normal and pathological retinal areas. This system is a useful tool for studying the cortical response to localized retinal stimulation and may shed light on various cortical plasticity processes.