Transepithelial Electrical Impedance Increase Following Porous Substrate Electroporation Enables Label-Free Delivery.

Porous substrate electroporation (PSEP) is a promising new method for intracellular delivery, yet fundamentals of PSEP are not well understood, especially the intermediate processes leading to delivery. PSEP is an electrical method, yet the relationship between PSEP and electrical impedance remains underexplored. In this study, a device capable of measuring impedance and performing PSEP is developed and the changes in transepithelial electrical impedance (TEEI) are monitored. These measurements show TEEI increases following PSEP, unlike other electroporation methods. The authors then demonstrate how cell culture conditions and electrical waveforms influence this response. More importantly, TEEI response features are correlated with viability and delivery efficiency, allowing prediction of outcomes without fluorescent cargo, imaging, or image processing. This label-free delivery also allows improved temporal resolution of transient processes following PSEP, which the authors expect will aid PSEP optimization for new cell types and cargos.

MiRNA-145-5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor.

The roles of specific microRNAs (miRNA) in oligodendrocyte (OL) differentiation have been studied in depth. However, miRNAs in OL precursors and oligodendrocyte progenitor cells (OPCs) have been less extensively investigated. MiR-145-5p is highly expressed in OPCs relative to differentiating OLs, suggesting this miRNA may serve a function specifically in OPCs. Knockdown of miR-145-5p in primary OPCs led to spontaneous differentiation, as evidenced by an increased proportion of MAG+ cells, increased cell ramification, and upregulation of multiple myelin genes including MYRF, TPPP, and MAG, and OL cell cycle exit marker Cdkn1c. Supporting this transition to a differentiating state, proliferation was reduced in miR-145-5p knockdown OPCs. Further, knockdown of miR-145-5p in differentiating OLs showed enhanced differentiation, with increased branching, myelin membrane production, and myelin gene expression. We identified several OL-specific genes targeted by miR-145-5p that exhibited upregulation with miR-145-5p knockdown, including myelin gene regulatory factor (MYRF), that could be regulating the prodifferentiation phenotype in both miR-145 knockdown OPCs and OLs. Indeed, spontaneous differentiation with knockdown of miR-145-5p was fully rescued by concurrent knockdown of MYRF. However, proliferation rate was only partially rescued with MYRF knockdown, and overexpression of miR-145-5p in OPCs increased proliferation rate without affecting expression of already lowly expressed differentiation genes. Taken together, these data suggest that in OPCs miR-145-5p both prevents differentiation at least in part by preventing expression of MYRF and promotes proliferation via as-yet-unidentified mechanisms. These findings clarify the need for differential regulation of miR-145-5p between OPCs and OLs and may have further implications in demyelinating diseases such as multiple sclerosis where miR-145-5p is dysregulated.

Quantum Break in High Intensity Gravitational Wave Interactions.

The lowest order amplitudes for [graviton+graviton → photon +photon] lead to cross sections of order G^{2}, where G is the gravitational constant. These are too small to be of any interest. However, in dense clouds of pure gravitons there are collective effects utilizing these same amplitudes that under the right circumstances can lead to copious production of photons.

Neutrino Cloud Instabilities Just above the Neutrino Sphere of a Supernova.

Most treatments of neutrino flavor evolution, above a surface of the last scattering, take identical angular distributions on this surface for the different initial (unmixed) flavors, and for particles and antiparticles. Differences in these distributions must be present, as a result of the species-dependent scattering cross sections lower in the star. These lead to a new set of nonlinear equations, unstable even at the initial surface with respect to perturbations that break all-over spherical symmetry. There could be important consequences for explosion dynamics as well as for the neutrino pulse in the outer regions.

The perils of Grandma's medication: colchicine toxicity causing pneumomediastinum.

A 19 year old male presented with a deliberate overdose of colchicine (50mg). He had no other significant medical history. 36 hours following admission he developed widespread surgical emphysema. An urgent CT scan of his chest and abdomen demonstrated mediastinal gas of lung origin. He also developed bone marrow suppression and disseminated intravascular coagulopathy. He was treated supportively with intravenous fluids, high flow oxygen and intravenous antibiotics and made a full recovery. Colchicine toxicity is a rare, but important presentation with high levels of morbidity and mortality. Pneumomediastinum is a potentially important complication. It may be appropriate to monitor patients in the later stages of the condition through an ambulatory setting.

Care management improves total cost of care for patients with dementia.

OBJECTIVES: To examine a 12-month dementia care management program's effect on health care cost, utilization, and overall return on investment in a Medicare managed care population. STUDY DESIGN: Pre-post analysis of participants (n = 121) enrolled in Ochsner's Care Ecosystem program from 2019 through 2021 compared with propensity-matched controls (n = 121). The primary outcome comparison was total cost of care. Secondary outcomes included components of total cost of care (eg, inpatient, outpatient, emergency department [ED] costs), health care utilization (eg, number of ED visits), and differences in Hierarchical Condition Category (HCC) risk scores. METHODS: Difference-in-differences analyses were conducted from baseline through 12 months comparing various financial metrics and utilization between groups. RESULTS: Care Ecosystem participants had significantly lower total cost of care at 12 months, mean savings of $475.80 per member per month compared with controls. Care Ecosystem participants had fewer ED, outpatient, and professional visits. HCC risk scores were also better relative to matched controls. CONCLUSIONS: A collaborative dementia care program demonstrated significant financial benefit in a managed Medicare population.

Nocardiosis in solid-organ transplant recipients: spectrum of imaging findings.

Nocardiosis is an infrequent but severe infection that primarily affects the lung and thence is able to produce disseminated disease. Prompt diagnosis of pulmonary and disseminated nocardiosis is of utmost importance in solid-organ transplant recipients to reduce mortality. Knowledge of the different radiological manifestations in the appropriate clinical setting is key to successful management of these patients. The aim of this review is to describe the radiological features of nocardiosis in immunosuppressed patients, particularly in solid-organ transplant recipients.

End-of-Life Experiences Within a Dementia Support Program During COVID-19: Context and Circumstances Surrounding Death During the Pandemic.

Background: Persons with dementia (PWD) and their caregivers are uniquely impacted by the COVID-19 pandemic, including higher risk of mortality for PWD. Objectives: To describe the context and circumstances of deaths of PWD within a dementia support program during the COVID-19 pandemic. Design: Retrospective data collection of PWD deaths between March 1, 2020 and February 28, 2021. Setting/Subjects: Decedents enrolled in Care Ecosystem, a multidisciplinary team model for dementia care at University of California San Francisco, Ochsner Health, and UCHealth. Measurements: Using mixed methods, we analyzed data using descriptive measures and team-based thematic analysis to understand the end-of-life (EOL) experience of PWD-caregiver dyads. Results: Twenty-nine PWD died across three sites. Almost half (45%) were between ages 70-79 and 12 (41%) were women. Eighteen (62%) died at a private residence; two died in the hospital. Hospice was involved for 22 (76%) patients. There were known causes of death for 15 (53%) patients. Only two deaths were directly related to COVID-19 infection. Social isolation was perceived to have a high or very high impact for 12 (41%) decedents. Four qualitative themes were identified: (1) isolation due to the pandemic, (2) changes in use of dementia supports and resources, (3) impact on goals of care decisions, and (4) communication challenges for EOL care coordination. Conclusion: Among PWD and caregivers enrolled in a dementia support program, the COVID-19 pandemic had direct and indirect influences on mortality and EOL experiences of PWD. Caregivers' experiences of caring, decision making, and bereavement were also affected.

Transepithelial Electrical Impedance Increase Following Porous Substrate Electroporation Enables Label-Free Delivery.

Porous substrate electroporation (PSEP) is a promising new method for intracellular delivery, yet fundamentals of the PSEP delivery process are not well understood, partly because most PSEP studies rely solely on imaging for evaluating delivery. Although effective, imaging alone limits understanding of intermediate processes leading to delivery. PSEP is an electrical process, so electrical impedance measurements naturally complement imaging for PSEP characterization. In this study, we developed a device capable of measuring impedance and performing PSEP and we monitored changes in transepithelial electrical impedance (TEEI). Our measurements show TEEI increases following PSEP, unlike other electroporation methods. We then demonstrated how cell culture conditions and electrical waveforms influence this response. More importantly, we correlated TEEI response features with viability and delivery efficiency, allowing prediction of outcomes without fluorescent cargo, imaging, or image processing. This label-free delivery also allows improved temporal resolution of transient processes following PSEP, which we expect will aid PSEP optimization for new cell types and cargos.

Combined inhibition of aromatase activity and dihydrotestosterone supplementation attenuates renal injury in male streptozotocin (STZ)-induced diabetic rats.

Our previous studies showed that streptozotocin (STZ)-induced diabetic male rats have increased estradiol and decreased testosterone levels that correlate with renal injury (Xu Q, Wells CC, Garman GH, Asico L, Escano CS, Maric C. Hypertension 51: 1218-1224, 2008). We further showed that either supplementing dihydrotestosterone (DHT) or inhibiting estradiol biosynthesis in these diabetic rats was only partially renoprotective (Manigrasso MB, Sawyer RT, Marbury DC, Flynn ER, Maric C. Am J Physiol Renal Physiol 301: F634-F640, 2011; Xu Q, Prabhu A, Xu S, Manigrassso MB, Maric C. Am J Physiol 297: F307-F315, 2009). The aim of this study was to test the hypothesis that the combined therapy of DHT supplementation and inhibition of estradiol synthesis would afford better renoprotection than either treatment alone. The study was performed in 12-wk-old male nondiabetic (ND), STZ-induced diabetic (D), and STZ-induced diabetic rats that received the combined therapy of 0.75 mg/day of DHT along with 0.15 mg · kg(-1) · day(-1) of an aromatase inhibitor, anastrozole (Dta), for 12 wk. Treatment with the combined therapy resulted in attenuation of albuminuria by 84%, glomerulosclerosis by 55%, and tubulointerstitial fibrosis by 62%. In addition, the combined treatment decreased the density of renal cortical CD68-positive cells by 70% and decreased protein expression of transforming growth factor-ß protein expression by 60%, collagen type IV by 65%, TNF-α by 55%, and IL-6 by 60%. We conclude that the combined treatment of DHT and blocking aromatase activity in diabetic male STZ-induced diabetic rats provides superior treatment than either treatment alone in the prevention of diabetic renal disease.

Renoprotective effects of C-peptide in the Dahl salt-sensitive rat.

Previous studies have demonstrated that renoprotective effects of C-peptide in experimental models of diabetes-induced renal disease may be mediated via lowering blood glucose. The present study examined the renoprotective effects of C-peptide in a model of nondiabetic renal disease, the Dahl salt-sensitive (SS/jr) rat. SS/jr rats were placed on a 2% NaCl diet for 2 wk (HS2, resulting in mild to moderate renal injury) or 4 wk (HS4, resulting in advanced renal injury) and then received either vehicle (veh) or C-peptide (Cpep) for additional 4 wk. Urine albumin (UAE) and protein (UPE) excretion rates were measured at baseline (i.e., before initiation of veh or Cpep treatment) and 4 wk later (i.e., at the time of death). Glomerular permeability, indexes of glomerulosclerosis and tubulointerstitial fibrosis, the presence of inflammatory cells, and protein expression of transforming growth factor-ß (TGF-ß) and podocin were measured at the time of death. In HS2 + veh rats, UAE and UPE increased by 74 and 92%, respectively, from baseline and the time of death. While HS2 + Cpep attenuated this increase in UAE and UPE, HS4 + Cpep had no effect on these parameters. Similarly, HS2 + Cpep reduced glomerular permeability, tubulointerstitial fibrosis, renal inflammation, TGF-ß, and podocin protein expression, while HS4 + Cpep had no effect. These studies indicate that C-peptide is renoprotective in nondiabetic experimental models with mild to moderate renal injury.

Cryptosporidium enteritis in solid organ transplant recipients: multicenter retrospective evaluation of 10 cases reveals an association with elevated tacrolimus concentrations.

BACKGROUND: Cryptosporidial enteritis, a diarrheal infection of the small intestine caused by the apicomplexan protozoa Cryptosporidium, is infrequently recognized in transplant recipients from developed countries. METHODS: A retrospective review of all cases of cryptosporidiosis in solid organ transplant (SOT) recipients at 2 centers from January 2001 to October 2010 was performed and compared with transplant recipients with community-onset Clostridium difficile infection (CDI). A literature search was performed with regard to reported cases of cryptosporidiosis in SOT recipients. RESULTS: Eight renal, 1 liver, and 1 lung transplant recipient were diagnosed with cryptosporidiosis at median 46.0 months (interquartile range [IQR] 25.2-62.8) following SOT. Symptoms existed for a median 14 days (IQR 10.5-14.8) before diagnosis. For the 9 patients receiving tacrolimus (TAC), mean TAC levels increased from 6.3 ± 1.1 to 21.3 ± 9.2 ng/mL (P = 0.0007) and median serum creatinine increased temporarily from 1.3 (IQR 1.1-1.7) to 2.4 (IQR 2.0-4.6) mg/dL (P = 0.008). By comparison, 8 SOT recipients (6 kidney, 2 liver) hospitalized with community-onset CDI had a mean TAC level of 10.8 ± 2.8 ng/dL during disease compared with 9.2 ± 2.3 ng/mL at baseline (P = 0.07) and had no change in median creatinine. All patients recovered from Cryptosporidium enteritis after receiving various chemotherapeutic regimens. CONCLUSIONS: Cryptosporidiosis should be recognized as an important cause of diarrhea after SOT and is associated with elevated TAC levels and acute kidney injury. Increased TAC levels may reflect altered drug metabolism in the small intestine.

Incidence of Early and Late-Onset Clostridioides difficile Infection following Appendectomy Compared to Other Common Abdominal Surgical Procedures.

Introduction: Clostridioides difficile associated diarrhea (CDAD) is a major public health issue. The appendix may function as a reservoir for the intestinal microbiome, which may repopulate the intestine following enteric infections including CDAD. Patients/Methods. This retrospective cohort study includes a total of 12,039 patients undergoing appendectomy, hemicolectomy, and cholecystectomy at a single center between 1992 and 2011 who were diagnosed with early and late-onset CDAD and were followed for a minimum of two years. Results: Cumulative CDAD rates were 2.3% after appendectomy, 6.4% after left and 6.8% after right hemicolectomy, and 4% after cholecystectomy with a median onset of 76 (range 1-6011) days after the procedure. Median time to CDAD onset was 76 days after appendectomy, 23 days after left, 54 days after right hemicolectomy, and 122 days after cholecystectomy (p < 0.05). Late-onset CDAD (>1 year) was significantly more common following appendectomy (37%) and cholecystectomy (39%) than after left (17%) and right (21%) hemicolectomy. Significant differences in age, gender, complication rate, and length of hospitalization between the four groups need to be considered when interpreting the results. Conclusion: The incidence of CDAD after various abdominal surgeries ranged between 2% and 7% in this study. Whereas, hemicolectomy patients had predominantly early onset CDAD, and appendectomy and cholecystectomy may increase the risk for late-onset CDAD. Appendectomy per se does not seem to increase the risk for late-onset CDAD.

Evaluating racial disparities in healthcare system utilization and caregiver burden among older adults with dementia.

OBJECTIVE: To evaluate racial differences in healthcare utilization and caregiver burden in a culturally diverse population of older adults with dementia. METHOD: One hundred and thirty-three dyads (person with dementia, PWD and caregiver, CG), with at least one emergency department (ED) visit or hospitalization 12 months prior, were enrolled. Independent sample t-tests and chi-squared analyses were performed to compare racial groups on healthcare utilization and CG burden. Mann-Whitney U test was used for item-level analyses, principal component analysis was used to examine relationships among outcomes, and regressions were used to identify the relationship between race and potential covariates. RESULTS: PWD sample mean age was 79 years, predominantly female, and with high school education. Racial distribution was 65% White and 35% Black. CG sample mean age was 64 years, predominantly female, with more than 12 years of education. No differences were found for age or dementia severity across racial groups. Black PWD experienced more ED and ambulance utilization when compared to White counterparts. Non-emergency hospitalization rates were higher for White PWD. No significant differences were found by race for CG burden total score; however, item-level analysis suggested more anger, reduced social life, uncertainty, and inadequacy in White CGs. Regressions demonstrated a positive relationship between Black race and adult-child CGs with increased ED visits, while dyad educational attainment was associated with hospitalizations independent of race. CONCLUSIONS: Healthcare utilization disparities extend to older adults with dementia diagnoses. Our findings suggest that culturally tailored interventions may be appropriate. Future research is encouraged to explore the effect of other covariates.

Small Vessel Disease, a Marker of Brain Health: What the Radiologist Needs to Know.

Small vessel disease, a disorder of cerebral microvessels, is an expanding epidemic and a common cause of stroke and dementia. Despite being almost ubiquitous in brain imaging, the clinicoradiologic association of small vessel disease is weak, and the underlying pathogenesis is poorly understood. The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria have standardized the nomenclature. These include white matter hyperintensities of presumed vascular origin, recent small subcortical infarcts, lacunes of presumed vascular origin, prominent perivascular spaces, cerebral microbleeds, superficial siderosis, cortical microinfarcts, and brain atrophy. Recently, the rigid categories among cognitive impairment, vascular dementia, stroke, and small vessel disease have become outdated, with a greater emphasis on brain health. Conventional and advanced small vessel disease imaging markers allow a comprehensive assessment of global brain heath. In this review, we discuss the pathophysiology of small vessel disease neuroimaging nomenclature by means of the STRIVE criteria, clinical implications, the role of advanced imaging, and future directions.

Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda.

Artemisinin partial resistance may facilitate selection of Plasmodium falciparum resistant to combination therapy partner drugs. We evaluated 99 P. falciparum isolates collected in 2021 from northern Uganda, where resistance-associated PfK13 C469Y and A675V mutations have emerged, and eastern Uganda, where these mutations are uncommon. With the ex vivo ring survival assay, isolates with the 469Y mutation (median survival 7.3% for mutant, 2.5% mixed, and 1.4% wild type) and/or mutations in Pfcoronin or falcipain-2a, had significantly greater survival; all isolates with survival >5% had mutations in at least one of these proteins. With ex vivo growth inhibition assays, susceptibility to lumefantrine (median IC50 14.6 vs. 6.9 nM, p < 0.0001) and dihydroartemisinin (2.3 vs. 1.5 nM, p = 0.003) was decreased in northern vs. eastern Uganda; 14/49 northern vs. 0/38 eastern isolates had lumefantrine IC50 > 20 nM (p = 0.0002). Targeted sequencing of 819 isolates from 2015-21 identified multiple polymorphisms associated with altered drug susceptibility, notably PfK13 469Y with decreased susceptibility to lumefantrine (p = 6 × 10-8) and PfCRT mutations with chloroquine resistance (p = 1 × 10-20). Our results raise concern regarding activity of artemether-lumefantrine, the first-line antimalarial in Uganda.

Inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induced diabetic rats.

We previously showed that the male streptozotocin (STZ)-induced diabetic rat exhibits decreased circulating testosterone and increased estradiol levels. While supplementation with dihydrotestosterone is partially renoprotective, the aim of the present study was to examine whether inhibition of estradiol synthesis, by blocking the aromatization of testosterone to estradiol using an aromatase inhibitor, can also prevent diabetes-associated renal injury. The study was performed on male Sprague-Dawley nondiabetic, STZ-induced diabetic, and STZ-induced diabetic rats treated with 0.15 mg/kg of anastrozole, an aromatase inhibitor (Da) for 12 wk. Treatment with anastrozole reduced diabetes-associated increases in plasma estradiol by 39% and increased plasma testosterone levels by 187%. Anastrozole treatment also attenuated urine albumin excretion by 42%, glomerulosclerosis by 30%, tubulointerstitial fibrosis by 32%, along with a decrease in the density of renal cortical CD68-positive cells by 50%, and protein expression of transforming growth factor-ß by 20%, collagen type IV by 29%, tumor necrosis factor-α by 28%, and interleukin-6 by 25%. Anastrozole also increased podocin protein expression by 18%. We conclude that blocking estradiol synthesis in male STZ-induced diabetic rats is renoprotective.

Nuclear fusion in dense matter.

The standard theory of nuclear fusion rates in strongly interacting plasmas can be (correctly) derived only when the energy release Q is large compared to other energies in the problem. We exhibit a result for rates that provides a basis for calculating the finite Q corrections. Crude estimates indicate a significant defect in the conventional results for some regions of high density and strong plasma coupling. We also lay some groundwork for a path integral calculation of the new effects.

Acceptability and Feasibility of a Multicomponent Telehealth Care Management Program in Older Adults With Advanced Dementia in a Residential Memory Care Unit.

The aim of the current study was to examine the acceptability and feasibility of a multicomponent care management program in older adults with advanced dementia in a long-term memory care unit. Eighteen older adults with moderate to severe dementia were asked to wear an activity monitor (Fitbit Charge 2 HR) and participate in a once monthly telehealth intervention via iPads over a 6-month period. Activity monitor data were used to assess compliance. Acceptability was assessed through qualitative interviews conducted with the caregiving staff on the memory unit. The care management program was acceptable to residents and their caregivers. Results indicated that the care management program is feasible in older adults with advanced dementia although activity monitor adherence was better during the day than at night. Telehealth session compliance was excellent throughout the study. A long-term multicomponent dementia care program is acceptable and feasible in individuals with advanced dementia. Future studies should aim to evaluate whether data received from activity monitors can be used in a dementia care intervention program.

Female Collegiate Dancers Body Composition, Macronutrient and Micronutrient Intake Over Two Academic Years: A Longitudinal Analysis.

Collegiate dancers face unique challenges to maintain a lean aesthetic, optimal diet, and a high-performance level due to the various stressors in college. The purpose of this study was to examine changes in body composition (BC) and diet over two years. Participants (N = 17, 19.6 ± 1.6 years) completed two laboratory sessions per semester. Sessions included height and weight, BC, dietary intake, and a health history questionnaire. Regardless of rigorous dance training and variations in the academic calendar, no significant changes in BC or diet were observed within semesters of over two years. BMI was normal (24.9 ± 4.1 kg/m2) with fat mass exceeding 30% at all timepoints. Fat mass was negatively correlated with carbohydrate, fat, and protein intake (g/kg/day; r = -0.291, p = 0.004; r = -0.372, p < 0.0001; r = -0.398, p < 0.0001; respectively). Energy intake was within the recommended daily allowance (2040 ± 710 kcal/day), however may be insufficient for an active dance population. Protein (1.1 ± 0.5 g/kg), carbohydrate (3.7 ± 1.6 g/kg), calcium (835 ± 405 mg/day), iron (17 ± 15 mg/day), and potassium (1628 ± 1736 mg/day) intake fell below recommendations for an active population. Alterations in dance training and the demands of the academic calendar may be contributing to suboptimal dietary intake and BC in female collegiate dancers.