Amplitude Parameters Are Predictive of Hearing Preservation in a Randomized Controlled Trial of Intracochlear Electrocochleography During Cochlear Implant Surgery.

OBJECTIVE: To prospectively evaluate the association between hearing preservation after cochlear implantation (CI) and intracochlear electrocochleography (ECochG) amplitude parameters. STUDY DESIGN: Multi-institutional, prospective randomized clinical trial. SETTING: Ten high-volume, tertiary care CI centers. PATIENTS: Adults (n = 87) with sensorineural hearing loss meeting CI criteria (2018-2021) with audiometric thresholds of ≤80 dB HL at 500 Hz. METHODS: Participants were randomized to CI surgery with or without audible ECochG monitoring. Electrode arrays were inserted to the full-depth marker. Hearing preservation was determined by comparing pre-CI, unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to LF-PTA at CI activation. Three ECochG amplitude parameters were analyzed: 1) insertion track patterns, 2) magnitude of ECochG amplitude change, and 3) total number of ECochG amplitude drops. RESULTS: The Type CC insertion track pattern, representing corrected drops in ECochG amplitude, was seen in 76% of cases with ECochG "on," compared with 24% of cases with ECochG "off" ( p = 0.003). The magnitude of ECochG signal drop was significantly correlated with the amount of LF-PTA change pre-CI and post-CI ( p < 0.05). The mean number of amplitude drops during electrode insertion was significantly correlated with change in LF-PTA at activation and 3 months post-CI ( p ≤ 0.01). CONCLUSIONS: ECochG amplitude parameters during CI surgery have important prognostic utility. Higher incidence of Type CC in ECochG "on" suggests that monitoring may be useful for surgeons in order to recover the ECochG signal and preventing potentially traumatic electrode-cochlear interactions.

Effect of Non-ablative Medical Therapy on Progression of Hearing Loss in Menière's Disease: A Systematic Review and meta-Analysis.

OBJECTIVE: To systematically review how audiometric data change over time in patients with Menière's disease (MD) undergoing non-ablative medical therapy. DATABASES REVIEWED: Medline (via PubMed), Scopus, Web of Science, Cumulated Index to Nursing and Allied Health Literature (CINAHL), Google Scholar. METHODS: A systematic review and meta-analysis of the literature was performed. Adult patients undergoing non-ablative medical therapy and reported duration of disease or follow-up were included and pooled estimates of pure-tone average (PTA) were tabulated. Studies were excluded if they did not use established MD, did not have pure-tone average (PTA) audiometric data, underwent ear surgery or ablative therapies, and were systematic reviews or case reports. RESULTS: Out of 198 articles meeting full eligibility, 13 studies, involving 950 patients with MD, were included in the review and further analyzed. No effect on progression of PTA from initial diagnosis was seen between the different medical therapies within 2 years of non-ablative medical treatment. There was a significant worsening of PTA after 2 year, regardless of treatment used. High levels of heterogeneity among studies were noted up to 6 months from diagnosis ( I2 = 79%), likely reflecting differences in patient characteristics, treatment regimens, and study design. Overall, the risk of bias was low for the majority of included studies. CONCLUSIONS: Patients diagnosed with MD who are undergoing non-ablative medical therapy should be counseled on the likelihood of worsening of hearing loss over the course of the disease despite elected treatment.

Vertiginous epilepsy in the pediatric population.

Vertiginous epilepsy (VE) is a rare and underrecognized epilepsy subtype in the pediatric population. Vertiginous symptoms are the sole or predominant feature, arise from the vestibular cortex, and seizures are usually brief. The incidence is estimated to be between six and 15 percent of pediatric patients presenting with dizziness. Diagnosis is often delayed for many years following the onset of symptoms, as there are no widely accepted diagnostic criteria. Diagnostic work-up should include a detailed history, physical exam, EEG, and brain imaging with MRI. Vestibular testing is helpful if peripheral vestibulopathy is suspected. Vertiginous epilepsy can have many possible causes, but a large majority are idiopathic or suspected to be genetic. Most patients with vertiginous epilepsy achieve seizure freedom with anti-seizure medications.

Efficacy and Health-Related Quality of Life Impact of Fecal Microbiota, Live-jslm: A Post Hoc Analysis of PUNCH CD3 Patients at First Recurrence of Clostridioides difficile Infection.

INTRODUCTION: Clostridioides difficile infection (CDI) causes symptoms of varying severity and negatively impacts patients' health-related quality of life (HRQL). Despite antibiotic treatment, recurrence of CDI (rCDI) is common and imposes clinical and economic burdens on patients. Fecal microbiota, live-jslm (REBYOTA [RBL]) is newly approved in the USA for prevention of rCDI following antibiotic treatments. We analyzed efficacy and HRQL impact of RBL vs. placebo in patients at first rCDI using data from the phase 3 randomized, double-blind placebo-controlled clinical trial, PUNCH CD3. METHODS: This post hoc analysis included patients at first rCDI fromPUNCH CD3. Treatment success (i.e., absence of diarrhea within 8 weeks post-treatment) was analyzed adjusting for baseline patient characteristics. HRQL was measured using the Clostridioides difficile Quality of Life Survey (Cdiff32); absolute scores and change from baseline in total and domain (physical, mental, and social) scores were summarized and compared between arms. Analyses were conducted for the trial's blinded phase only. RESULTS: Among 86 eligible patients (32.8% of the overall trial population, RBL 53 [61.6%], placebo 33 [38.4%]), RBL-treated patients had significantly lower odds of recurrence (i.e., greater probability of treatment success) at week 8 vs. placebo (odds ratio 0.35 [95% confidence interval 0.13, 0.98]). Probability of treatment success at week 8 was 81% for RBL and 60% for placebo, representing 21% absolute and 35% relative increases for RBL (crude proportions 79.2% vs. 60.6%; relative risk 0.53, p = 0.06). Additionally, RBL was associated with significantly higher Cdiff32 total (change score difference 13.5 [standard deviation 5.7], p < 0.05) and mental domain (16.2 [6.0], p < 0.01) scores vs. placebo from baseline to week 8. CONCLUSION: Compared to placebo, RBL demonstrated a significantly higher treatment success in preventing further rCDI and enhanced HRQL among patients at first recurrence, establishing RBL as an effective treatment to prevent further recurrences in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03244644.

Recent advances in catalytic and non-catalytic epoxidation of terpenes: a pathway to bio-based polymers from waste biomass.

Epoxides derived from waste biomass are a promising avenue for the production of bio-based polymers, including polyamides, polyesters, polyurethanes, and polycarbonates. This review article explores recent efforts to develop both catalytic and non-catalytic processes for the epoxidation of terpene, employing a variety of oxidizing agents and techniques for process intensification. Experimental investigations into the epoxidation of limonene have shown that these methods can be extended to other terpenes. To optimize the epoxidation of bio-based terpene, there is a need to develop continuous processes that address limitations in mass and heat transfer. This review discusses flow chemistry and innovative reactor designs as part of a multi-scale approach aimed at industrial transformation. These methods facilitate continuous processing, improve mixing, and either eliminate or reduce the need for solvents by enhancing heat transfer capabilities. Overall, the objective of this review is to contribute to the development of commercially viable processes for producing bio-based epoxides from waste biomass.

Effect of Fecal Microbiota, Live-Jslm (REBYOTA [RBL]) on Health-Related Quality of Life in Patients With Recurrent Clostridioides difficile Infection: Results From the PUNCH CD3 Clinical Trial.

Background: Recurrence of Clostridioides difficile infection (rCDI) is common, prolonging disease morbidity and leading to poor quality of life. We evaluated disease-specific health-related quality of life (HRQL) in patients with rCDI treated with fecal microbiota, live-jslm (REBYOTA [RBL]; Rebiotix) versus placebo. Methods: This was a secondary analysis of a randomized, double-blind, placebo-controlled phase 3 study (PUNCH CD3). The disease-specific Clostridioides difficile Quality of Life Survey (Cdiff32) was administered at baseline and at weeks 1, 4, and 8. Changes in Cdiff32 total and domain (physical, mental, social) scores from baseline to week 8 were compared between RBL and placebo and for responders and nonresponders. Results: Findings were analyzed in a total of 185 patients (RBL, n = 128 [69.2%]; placebo, n = 57 [30.8%]) with available Cdiff32 data. Patients from both arms showed significant improvements in Cdiff32 scores relative to baseline across all outcomes and at all time points (all P < .001); RBL-treated patients showed significantly greater improvements in mental domain than those receiving placebo. In adjusted analyses, RBL-treated patients showed greater improvements than placebo in total score and physical and mental domains (all P < .05). Similar improvement in mental domain was observed among responders, while nonresponders showed numerical improvements with RBL but not placebo. Conclusions: In a phase 3 double-blinded clinical trial, RBL-treated patients reported more substantial and sustained disease-specific HRQL improvements than placebo-treated patients. Clinical Trials Registration: ClinicalTrials.gov NCT03244644 (https://clinicaltrials.gov/ct2/show/NCT03244644).

Ventricular fibrillation waveform properties influenced by thoracic impedance guided chest compressions in a porcine model.

BACKGROUND AND OBJECTIVE: Quantitative measures extracted from ventricular fibrillation (VF) waveform reflect the metabolic state of the myocardium and are associated with survival outcome. The quality of delivered chest compressions during cardiopulmonary resuscitation are also linked with survival. The aim of this research is to explore the viability and effectiveness of a thoracic impedance (TI) based chest compression (CC) guidance system to control CC depth within individual subjects and influence VF waveform properties. METHODS: This porcine investigation includes an analysis of two protocols. CC were delivered in 2 min episodes at a constant rate of 110 CC min-1. Subject-specific CC depth was controlled using a TI-thresholding system where CC were performed according to the amplitude (ZRMS, 0.125 to 1.250 Ω) of a band-passed TI signal (ZCC). Protocol A was a retrospective analysis of a 12-porcine study to characterise the response of two VF waveform metrics: amplitude spectrum area (AMSA) and mean slope (MS), to varying CC quality. Protocol B was a prospective 12-porcine study to determine if changes in VF waveform metrics, due to CC quality, were associated with defibrillation outcome. RESULTS: Protocol A: A directly proportional relationship was observed between ZRMS and CC depth applied within each subject (r = 0.90; p <0.001). A positive relationship was observed between ZRMS and both AMSA (p <0.001) and MS (p <0.001), where greater TI thresholds were associated with greater waveform metrics. PROTOCOL B: MS was associated with return of circulation following defibrillation (odds ratio = 2.657; p = 0.043). CONCLUSION: TI-thresholding was an effective way to control CC depth within-subjects. Compressions applied according to higher TI thresholds evoked an increase in AMSA and MS. The response in MS due to deeper CC resulted in a greater incidence of ROSC compared to shallow chest compressions.

Synthesis of cyclic carbonates from CO2 cycloaddition to bio-based epoxides and glycerol: an overview of recent development.

Anthropogenic carbon dioxide (CO2) emissions contribute significantly to global warming and deplete fossil carbon resources, prompting a shift to bio-based raw materials. The two main technologies for reducing CO2 emissions are capturing and either storing or utilizing it. However, while capture and storage have high reduction potential, they lack economic feasibility. Conversely, by utilizing the CO2 captured from streams and air to produce valuable products, it can become an asset and curb greenhouse gas effects. CO2 is a challenging C1-building block due to its high kinetic inertness and thermodynamic stability, requiring high temperature and pressure conditions and a reactive catalytic system. Nonetheless, cyclic carbonate production by reacting epoxides and CO2 is a promising green and sustainable chemistry reaction, with enormous potential applications as an electrolyte in lithium-ion batteries, a green solvent, and a monomer in polycarbonate production. This review focuses on the most recent developments in the synthesis of cyclic carbonates from glycerol and bio-based epoxides, as well as efficient methods for chemically transforming CO2 using flow chemistry and novel reactor designs.

Safety of fecal microbiota, live-jslm (REBYOTA™) in individuals with recurrent Clostridioides difficile infection: data from five prospective clinical trials.

Background: Microbiota-based treatments reduce the incidence of recurrent Clostridioides difficile infections (rCDIs), but prospectively collected safety data needed to broaden patient access and protect public health have been limited. Objectives: We provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) - the first microbiota-based live biotherapeutic product approved by the US Food and Drug Administration - for preventing rCDI in adults. Design: Integrated safety analysis includes three phase II trials (PUNCH CD, PUNCH CD2, PUNCH Open-Label) and two phase III trials (PUNCH CD3, PUNCH CD3-OLS) of RBL. Methods: Trial participants were at least 18 years of age with documented rCDI who completed standard-of-care antibiotic therapy before treatment with RBL. Assigned study treatment regimen was one or two doses of RBL (or placebo) administered rectally, depending on the trial design. In four of the five trials, participants with CDI recurrence within 8 weeks after RBL or placebo administration were eligible for treatment with open-label RBL. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; in PUNCH CD2 and PUNCH Open-Label trials, TEAEs and serious TEAEs were collected through 12 and 24 months, respectively. Results: Among the five trials, 978 participants received at least one dose of RBL (assigned treatment or after recurrence) and 83 participants received placebo only. TEAEs were reported in 60.2% of Placebo Only participants and 66.4% of RBL Only participants. Only abdominal pain, nausea, and flatulence were significantly higher in the RBL Only group compared with the Placebo Only group. Most TEAEs were mild or moderate in severity and were most frequently related to preexisting conditions. There were no reported infections for which the causative pathogen was traced to RBL. Potentially life-threatening TEAEs were infrequent (3.0% of participants). Conclusion: Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL.

Vasoprotective effects of NOX4 are mediated via polymerase and transient receptor potential melastatin 2 cation channels in endothelial cells.

BACKGROUND: NOX4 activation has been implicated to have vasoprotective and blood pressure (BP)-lowering effects. Molecular mechanisms underlying this are unclear, but NOX4-induced regulation of the redox-sensitive Ca 2+ channel TRPM2 and effects on endothelial nitric oxide synthase (eNOS)-nitric oxide signalling may be important. METHOD: Wild-type and LinA3, renin-expressing hypertensive mice, were crossed with NOX4 knockout mice. Vascular function was measured by myography. Generation of superoxide (O 2- ) and hydrogen peroxide (H 2 O 2 ) were assessed by lucigenin and amplex red, respectively, and Ca 2+ influx by Cal-520 fluorescence in rat aortic endothelial cells (RAEC). RESULTS: BP was increased in NOX4KO, LinA3 and LinA3/NOX4KO mice. This was associated with endothelial dysfunction and vascular remodelling, with exaggerated effects in NOX4KO groups. The TRPM2 activator, ADPR, improved vascular relaxation in LinA3/NOX4KO mice, an effect recapitulated by H 2 O 2 . Inhibition of PARP and TRPM2 with olaparib and 2-APB, respectively, recapitulated endothelial dysfunction in NOX4KO. In endothelial cells, Ang II increased H 2 O 2 generation and Ca 2+ influx, effects reduced by TRPM2 siRNA, TRPM2 inhibitors (8-br-cADPR, 2-APB), olaparib and GKT137831 (NOX4 inhibitor). Ang II-induced eNOS activation was blocked by NOX4 and TRPM2 siRNA, GKT137831, PEG-catalase and 8-br-cADPR. CONCLUSION: Our findings indicate that NOX4-induced H 2 O 2 production activates PARP/TRPM2, Ca 2+ influx, eNOS activation and nitric oxide release in endothelial cells. NOX4 deficiency impairs Ca 2+ homeostasis leading to endothelial dysfunction, an effect exacerbated in hypertension. We define a novel pathway linking endothelial NOX4/H 2 O 2 to eNOS/nitric oxide through PARP/TRPM2/Ca 2+ . This vasoprotective pathway is perturbed when NOX4 is downregulated and may have significance in conditions associated with endothelial dysfunction, including hypertension.

Retrospective Analysis of the Safety and Efficacy of Fecal Microbiota, Live-jslm (REBYOTATM) Administered Under Enforcement Discretion to Patients With Clostridioides difficile Infection.

Background: Fecal microbiota, live-jslm (RBL; REBYOTA™), the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent Clostridioides difficile infection (rCDI) in adults, has been evaluated in 5 prospective clinical trials. A retrospective analysis considered the safety and efficacy of RBL administered under US Food and Drug Administration enforcement discretion to patients with rCDI and broad eligibility criteria mimicking real-world practice. Methods: We retrospectively identified adults with rCDI treated with RBL under enforcement discretion between November 1, 2015, and September 30, 2019, across 5 study sites. CDI diagnosis was based on site-specific practice. The primary safety set (PSS) included all patients who were naïve to previous RBL treatment and had continuously comprehensive medical records for 6 months following treatment. Results: The primary treatment cohort had 94 patients; the PSS included 64 patients with common comorbidities receiving diverse chronic therapeutics. Most treatment-emergent adverse events were mild to moderate in severity and comparable between comorbidity subgroups and the overall population. There were no serious adverse events related to RBL or the administration procedure. In the PSS, 82.8% of RBL-treated patients responded at 8 weeks, of whom 88.7% had sustained response through 6 months. The number of RBL doses administered had no marked effect on outcome. Conclusions: Together with prospective clinical trial outcomes, these findings support the efficacy and safety of RBL to prevent rCDI, with diagnostics and comorbidities representative of real-world clinical practice.

Synergistic effect of plasma power and temperature on the cracking of toluene in the N2 based product gas.

In this research, a dielectric barrier discharge (DBD) reactor is used to study the cracking of the toluene into C1-C6 hydrocarbons. The combined effect of parameters such as temperature (20-400 °C) and plasma power (10-40 W) was investigated to evaluate the DBD reactor performance. The main gaseous products from the decomposition of toluene include lower hydrocarbon (C1-C6). The cracking of toluene increases with power at all temperatures (20-400 °C). On the otherhand, it decreases from 92.8 to 73.1% at 10 W, 97.2 to 80.5% at 20, 97.5 to 86.5% at 30 W, and 98.4 to 93.7% at 40 W with raising the temperature from 20 to 400 °C. Nonetheless, as the temperature and plasma input power increase, the methane yield increases. At 40 W, the maximum methane yield was 5.1%. At 10 and 20 W, the selectivity to C2 increases as the temperature rises up to 400 °C. At 30 and 40 W, it began to drop after 300 °C due to the formation of methane and the yield of methane increases significantly beyond this temperature.

Temporal analysis of continuous chest compression rate and depth performed by firefighters during out of hospital cardiac arrest.

BACKGROUND: Quality of chest compressions (CC) during cardiopulmonary resuscitation (CPR) often do not meet guideline recommendations for rate and depth. This may be due to the fatiguing nature of physically compressing a patient's chest, meaning that CPR quality reduces over time. OBJECTIVE: This analysis investigates the effect of CPR duration on the performance of continuous CCs delivered by firefighters equipped with CPR feedback devices. METHODS: Data were collected from a first responder group which used CPR feedback and automatic external defibrillator devices when attending out-of-hospital cardiac arrest events. Depth and rate of CC were analysed for 134 patients. Mean CC depth and rate were calculated every 5 s during two-minute episodes of CPR. Regression models were created to evaluate the relationship between applied CC depth and rate as a function of time. RESULTS: Mean (SD) CC depth during the investigation was 48 (9) mm. An inverse relationship was observed between CC depth and CPR duration, where CC depth decreased by 3.39 mm, over two-minutes of CPR (p < 0.001). Mean (SD) CC rate was 112.06 (5.87) compressions per minute. No significant relationship was observed between CC rate and CPR duration (p = 0.077). Mean depth was within guideline range for 33.58% of patient events, while guideline rate was observed in 92.54% of cases. CONCLUSIONS: A reduction in CC depth was observed during two-minutes of continuous CCs while CC rate was not affected. One third of patients received a mean CC depth within guideline range (50 to 60 mm).

Microbiota-Based Live Biotherapeutic RBX2660 for the Reduction of Recurrent Clostridioides difficile Infection in Older Adults With Underlying Comorbidities.

Background: Advanced age and underlying comorbidities are associated with greater rates of recurrence in patients with Clostridioides difficile infection (CDI). Reducing the likelihood of recurrence through treatment with an antimicrobial followed by a microbiota replacement therapy can decrease the burden of this infection and improve patient outcomes. We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in older adults with recurrent CDI, grouped by comorbidities. Methods: In this post hoc subgroup analysis of the PUNCH CD3 trial, we assessed outcomes in older adults (age ≥65 years) grouped by Charlson Comorbidity Index severity scores at screening (moderate [3-4] and severe [≥5]) and by the presence of underlying cardiac, renal, or gastrointestinal disorders. Results: RBX2660 treatment success rates in older adults with comorbidities were consistent across subgroups and similar to those in the total RBX2660-treated population. A greater percentage of RBX2660-treated older adults remained free of CDI recurrence through 8 weeks following treatment compared with placebo-treated participants in all but 2 subgroups assessed. Across all subgroups, most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and related to a preexisting condition. None of the serious or life-threatening TEAEs that occurred were related to RBX2660 or its administration. Occurrence of TEAEs did not cluster in any subgroup. Conclusions: RBX2660 is efficacious and safe in older adults with recurrent CDI and underlying comorbidities.

The Demographics of Menière's Disease: Selection Bias or Differential Susceptibility?

OBJECTIVE: To clarify whether the reported lack of racial and ethnic diversity among Menière's disease (MD) patients is representative of selection bias or disease susceptibility. STUDY DESIGN: Retrospective medical record review and population-level analyses. SETTING: Tertiary referral center. PATIENTS: Cohort of 1091 patients diagnosed with MD by the tertiary otology service. MAIN OUTCOME MEASURE: Demographic and population-level characteristics (age, sex, race, insurance status, ZIP code, median income, education level) compared with local, regional, health system, and otolaryngology clinic demographics. RESULTS: Patients seen for MD were significantly older than those seen throughout the otolaryngology clinic (median, 65.0 versus 58.8 yr) or health system (65.0 versus 50.8 yr). A majority of patients with MD were of White race (92%), compared with 2.7% Black race and 0.5% Asian. Using population-level data, median income and having medical insurance were significantly correlated with care for MD. A disproportionate rate of care for MD was seen in ZIP codes outside urban areas as compared with other otologic and otolaryngologic conditions seen in the same clinic. CONCLUSION: Patients with MD are of older age, more likely to be of White race, and disproportionately from rural locales. The demographic profile of patients diagnosed with MD by tertiary otology is better explained by differential susceptibility to MD than by selection bias.

A foam column system harvesting freshwater algae for biodiesel production: An experiment and process model evaluations.

The purpose of this study was to examine the application of the mathematical model of drift flux to the experimental results of the effect of cationic trimethyl-ammonium bromide (CTAB)-aided continuous foam flotation harvesting on the lipid content in Chlorella vulgaris microalgae. An experiment was conducted to determine the effect of the operating conditions on the enrichment factor (EF) and percentage recovery efficiency (%RE), where the flow rates at the inlet and bottom outlet remained constant. Data for the binary system (without algae) and ternary system (with algae) in an equal-area foam column show that the EF decreases linearly with increasing initial CTAB concentrations ranging from 30 to 75 mg/L for three levels of the studied air volumetric flow rate range (1-3) L/min. The percentage harvesting efficiency increased with increasing initial CTAB concentration and air volumetric flow rate to 96 % in the binary systems and 94 % in the ternary systems. However, in the foam column with the riser used in the three systems, a lower volume of liquid foam in the upward outlet stream resulted in a lower RE% than that of the column without the riser. The objective function of EF for the system with algae increased when the initial CTAB concentration was increased from 30 to 45 mg/L in the foam column with a riser for all air flow rates, and after 45 mg/L, a sudden drop in the microalgae EF was observed. In the comparison between the foam column with and without the riser for the system with algae, the optimum EF was 145 for the design of the column with the riser and 139 for the column without the riser.

ATRX modulates the escape from a telomere crisis.

Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT) that leads to long and heterogenous telomere length distributions. Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene are frequently found in ALT cancers. Here, we demonstrate that the loss of ATRX, coupled with telomere dysfunction during crisis, is sufficient to initiate activation of the ALT pathway and that it confers replicative immortality in human fibroblasts. Additionally, loss of ATRX combined with a telomere-driven crisis in HCT116 epithelial cancer cells led to the initiation of an ALT-like pathway. In these cells, a rapid and precise telomeric elongation and the induction of C-circles was observed; however, this process was transient and the telomeres ultimately continued to erode such that the cells either died or the escape from crisis was associated with telomerase activation. In both of these instances, telomere sequencing revealed that all alleles, irrespective of whether they were elongated, were enriched in variant repeat types, that appeared to be cell-line specific. Thus, our data show that the loss of ATRX combined with telomere dysfunction during crisis induces the ALT pathway in fibroblasts and enables a transient activation of ALT in epithelial cells.

Remote synchronous usability testing of public access defibrillators during social distancing in a pandemic.

Public access automated external defibrillators (AEDs) represent emergency medical devices that may be used by untrained lay-persons in a life-critical event. As such their usability must be confirmed through simulation testing. In 2020 the novel coronavirus caused a global pandemic. In order to reduce the spread of the virus, many restrictions such as social distancing and travel bans were enforced. Usability testing of AEDs is typically conducted in-person, but due to these restrictions, other usability solutions must be investigated. Two studies were conducted, each with 18 participants: (1) an in-person usability study of an AED conducted in an office space, and (2) a synchronous remote usability study of the same AED conducted using video conferencing software. Key metrics associated with AED use, such as time to turn on, time to place pads and time to deliver a shock, were assessed in both studies. There was no difference in time taken to turn the AED on in the in-person study compared to the remote study, but the time to place electrode pads and to deliver a shock were significantly lower in the in-person study than in the remote study. Overall, the results of this study indicate that remote user testing of public access defibrillators may be appropriate in formative usability studies for determining understanding of the user interface.

TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt.

Hyperaldosteronism causes cardiovascular disease as well as hypomagnesemia. Mechanisms are ill-defined but dysregulation of TRPM7, a Mg2+-permeable channel/α-kinase, may be important. We examined the role of TRPM7 in aldosterone-dependent cardiovascular and renal injury by studying aldosterone-salt treated TRPM7-deficient (TRPM7+/Δkinase) mice. Plasma/tissue [Mg2+] and TRPM7 phosphorylation were reduced in vehicle-treated TRPM7+/Δkinase mice, effects recapitulated in aldosterone-salt-treated wild-type mice. Aldosterone-salt treatment exaggerated vascular dysfunction and amplified cardiovascular and renal fibrosis, with associated increased blood pressure in TRPM7+/Δkinase mice. Tissue expression of Mg2+-regulated phosphatases (PPM1A, PTEN) was downregulated and phosphorylation of Smad3, ERK1/2, and Stat1 was upregulated in aldosterone-salt TRPM7-deficient mice. Aldosterone-induced phosphorylation of pro-fibrotic signaling was increased in TRPM7+/Δkinase fibroblasts, effects ameliorated by Mg2+ supplementation. TRPM7 deficiency amplifies aldosterone-salt-induced cardiovascular remodeling and damage. We identify TRPM7 downregulation and associated hypomagnesemia as putative molecular mechanisms underlying deleterious cardiovascular and renal effects of hyperaldosteronism.