Ventilator Weaning and Terminal Extubation: Withdrawal of Life-Sustaining Therapy in Children. Secondary Analysis of the Death One Hour After Terminal Extubation Study.

OBJECTIVE: Terminal extubation (TE) and terminal weaning (TW) during withdrawal of life-sustaining therapies (WLSTs) have been described and defined in adults. The recent Death One Hour After Terminal Extubation study aimed to validate a model developed to predict whether a child would die within 1 hour after discontinuation of mechanical ventilation for WLST. Although TW has not been described in children, pre-extubation weaning has been known to occur before WLST, though to what extent is unknown. In this preplanned secondary analysis, we aim to describe/define TE and pre-extubation weaning (PW) in children and compare characteristics of patients who had ventilatory support decreased before WLST with those who did not. DESIGN: Secondary analysis of multicenter retrospective cohort study. SETTING: Ten PICUs in the United States between 2009 and 2021. PATIENTS: Nine hundred thirteen patients 0-21 years old who died after WLST. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 71.4% ( n = 652) had TE without decrease in ventilatory support in the 6 hours prior. TE without decrease in ventilatory support in the 6 hours prior = 71.4% ( n = 652) of our sample. Clinically relevant decrease in ventilatory support before WLST = 11% ( n = 100), and 17.6% ( n = 161) had likely incidental decrease in ventilatory support before WLST. Relevant ventilator parameters decreased were F io2 and/or ventilator set rates. There were no significant differences in any of the other evaluated patient characteristics between groups (weight, body mass index, unit type, primary diagnostic category, presence of coma, time to death after WLST, analgosedative requirements, postextubation respiratory support modality). CONCLUSIONS: Decreasing ventilatory support before WLST with extubation in children does occur. This practice was not associated with significant differences in palliative analgosedation doses or time to death after extubation.

Mode of carbon and energy metabolism shifts lipid composition in the thermoacidophile Acidianus.

The degree of cyclization, or ring index (RI), in archaeal glycerol dibiphytanyl glycerol tetraether (GDGT) lipids was long thought to reflect homeoviscous adaptation to temperature. However, more recent experiments show that other factors (e.g., pH, growth phase, and energy flux) can also affect membrane composition. The main objective of this study was to investigate the effect of carbon and energy metabolism on membrane cyclization. To do so, we cultivated Acidianus sp. DS80, a metabolically flexible and thermoacidophilic archaeon, on different electron donor, acceptor, and carbon source combinations (S0/Fe3+/CO2, H2/Fe3+/CO2, H2/S0/CO2, or H2/S0/glucose). We show that differences in energy and carbon metabolism can result in over a full unit of change in RI in the thermoacidophile Acidianus sp. DS80. The patterns in RI correlated with the normalized electron transfer rate between the electron donor and acceptor and did not always align with thermodynamic predictions of energy yield. In light of this, we discuss other factors that may affect the kinetics of cellular energy metabolism: electron transfer chain (ETC) efficiency, location of ETC reaction components (cytoplasmic vs. extracellular), and the physical state of electron donors and acceptors (gas vs. solid). Furthermore, the assimilation of a more reduced form of carbon during heterotrophy appears to decrease the demand for reducing equivalents during lipid biosynthesis, resulting in lower RI. Together, these results point to the fundamental role of the cellular energy state in dictating GDGT cyclization, with those cells experiencing greater energy limitation synthesizing more cyclized GDGTs.IMPORTANCESome archaea make unique membrane-spanning lipids with different numbers of five- or six-membered rings in the core structure, which modulate membrane fluidity and permeability. Changes in membrane core lipid composition reflect the fundamental adaptation strategies of archaea in response to stress, but multiple environmental and physiological factors may affect the needs for membrane fluidity and permeability. In this study, we tested how Acidianus sp. DS80 changed its core lipid composition when grown with different electron donor/acceptor pairs. We show that changes in energy and carbon metabolisms significantly affected the relative abundance of rings in the core lipids of DS80. These observations highlight the need to better constrain metabolic parameters, in addition to environmental factors, which may influence changes in membrane physiology in Archaea. Such consideration would be particularly important for studying archaeal lipids from habitats that experience frequent environmental fluctuations and/or where metabolically diverse archaea thrive.

A randomized trial of blood donor iron repletion on red cell quality for transfusion and donor cognition and well-being.

Although altruistic regular blood donors are vital for the blood supply, many become iron deficient from donation-induced iron loss. The effects of blood donation-induced iron deficiency on red cell transfusion quality or donor cognition are unknown. In this double-blind, randomized trial, adult iron-deficient blood donors (n = 79; ferritin < 15 µg/L and zinc protoporphyrin >60 µMol/mol heme) who met donation qualifications were enrolled. A first standard blood donation was followed by the gold-standard measure for red cell storage quality: a 51-chromium posttransfusion red cell recovery study. Donors were then randomized to intravenous iron repletion (1 g low-molecular-weight iron dextran) or placebo. A second donation ∼5 months later was followed by another recovery study. Primary outcome was the within-subject change in posttransfusion recovery. The primary outcome measure of an ancillary study reported here was the National Institutes of Health Toolbox-derived uncorrected standard Cognition Fluid Composite Score. Overall, 983 donors were screened; 110 were iron-deficient, and of these, 39 were randomized to iron repletion and 40 to placebo. Red cell storage quality was unchanged by iron repletion: mean change in posttransfusion recovery was 1.6% (95% confidence interval -0.5 to 3.8) and -0.4% (-2.0 to 1.2) with and without iron, respectively. Iron repletion did not affect any cognition or well-being measures. These data provide evidence that current criteria for blood donation preserve red cell transfusion quality for the recipient and protect adult donors from measurable effects of blood donation-induced iron deficiency on cognition. This trial was registered at www.clinicaltrials.gov as NCT02889133 and NCT02990559.

Outcomes of Heart Transplant Using High Donor Sequence Number Offers.

INTRODUCTION: Higher donor sequence numbers (DSNs) might spark provider concern about poor donor quality. We evaluated characteristics of high-DSN offers used for transplant and compared outcomes of high- and low-DSN transplants. MATERIALS AND METHODS: Adult isolated heart transplants between January 1, 2015, and December 31, 2022, were identified from the organ procurement and transplantation network database and stratified into high (≥42) and low (<42) DSN. Postoperative outcomes, including predischarge complications, hospital length of stay, and survival at 1 and 3 y, were evaluated using multivariable regressions. RESULTS: A total of 21,217 recipients met the inclusion criteria, with 2131 (10.0%) classified as high-DSN. Donor factors associated with greater odds of high-DSN at acceptance included older age, higher creatinine, diabetes, hypertension, and lower left ventricular ejection fraction. Recipients accepting high-DSN offers were older and more likely to be female, of blood type O, and have lower status at transplant. High- and low-DSN transplants had similar likelihood of stroke (3.2% versus 3.5%; P = 0.97), dialysis (12.3% versus 13.5%; P = 0.12), pacemaker implant (2.3% versus 2.1%; P = 0.64), had similar lengths of stay (16 [12-24] versus 16 [12-25] days, P = 0.38), and survival at 1 (91.6% versus 91.6%; aHR 0.85 [0.72-1.02], P = 0.08) and 3 y (84.2% versus 85.1%; aHR 0.91 [0.79-1.05], P = 0.21) post-transplant. CONCLUSIONS: High-DSN (≥42) was not an independent risk factor for post-transplant mortality and should not be the sole deterrent to acceptance. Accepting high-DSN organs may increase access to transplantation for lower-status candidates.

Evolving Barriers to Clinical Trial Enrollment and Clinical Care in Neuro-oncology in the Face of COVID-19.

The lack of treatments with durable response in neuro-oncology highlights the critical need for clinical trials to advance patient care. The intersection of relatively low incidence, evolving classification schema, and entrenched community, healthcare provider, and organizational factors have been historic challenges against successful trial enrollment and implementation. The additional need for multidisciplinary, often tertiary-level care, further magnifies latent national and international health inequities with rural and under-served populations. The COVID-19 pandemic both unveiled fundamental weaknesses in historical approaches and prompted the necessity of new approaches and systems for conducting clinical trials. Here, we provide an overview of traditional barriers to clinical trial enrollment in neuro-oncology, the effect of COVID-19 on these barriers, and the discovery of additional systemic weaknesses. Finally, we discuss future directions by reflecting on lessons learned with strategies to broaden access of care and streamline clinical trial integration into clinical practice.

Comparison of Minimally Invasive Procedures for Benign Prostatic Hyperplasia: A Cost-effectiveness Analysis.

Background Benign prostatic hyperplasia (BPH) is a disease that affects millions of U.S. men and is costly to treat. Purpose To compare the cost-effectiveness of four minimally invasive therapies (MITs) and medical management for the treatment of BPH. Materials and Methods A cost-effectiveness analysis from a payer's perspective with Markov modeling was performed, comparing prostatic artery embolization (PAE), prostatic urethral lift, aquablation, water vapor thermal therapy, and medical management for BPH spanning a time horizon of 5 years. The model incorporated the probability of procedural complications and recurrent symptoms necessitating retreatment, which were extracted from published studies with long-term follow-up. Costs were based on Medicare reimbursements using CPT codes for ambulatory surgery centers. Outcomes were measured using the quality-adjusted life year (QALY), incorporating both life quality and expectancy. Statistical analyses included a base case calculation (using the most probable value of each parameter) and probabilistic and deterministic sensitivity analyses. Results In the base case calculation, outcomes for the strategies were comparable, with a difference of 0.030 QALY (11 days of life in perfect health) between the most (PAE) and least (medical management) effective strategies. PAE was the most cost-effective strategy relative to medical management, with an incremental cost-effectiveness ratio of $64 842 per QALY. Probabilistic sensitivity analysis showed PAE was more cost-effective compared with prostatic urethral lift, aquablation, water vapor therapy, and medical management in pairwise comparisons. In sensitivity analysis of retreatment risk, PAE remained the most cost-effective strategy until its repeat treatment rates exceeded 2.30% per 6 months, at which point water vapor therapy became the optimal choice. PAE was the most cost-effective procedure when its procedural cost was lower than $4755. Aquablation and prostatic urethral lift became more cost-effective when their procedural costs were lower than $3015 and $1097, respectively. Conclusion This modeling-based study showed that PAE appears to be a cost-effective modality among medical management and MITs for patients with BPH, with comparable outcomes to prostatic urethral lift, water vapor therapy, and aquablation at a lower expected cost. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Gemmete in this issue.

The impact of a statewide payment reform on transcatheter aortic valve replacement (TAVR) utilization and readmissions.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an increasingly used but relatively expensive procedure with substantial associated readmission rates. It is unknown how cost-constrictive payment reform measures, such as Maryland's All Payer Model, impact TAVR utilization given its relative expense. This study investigated the impact of Maryland's All Payer Model on TAVR utilization and readmissions among Maryland Medicare beneficiaries. METHODS: This was a quasi-experimental investigation of Maryland Medicare patients undergoing TAVR between 2012 and 2018. New Jersey data were used for comparison. Longitudinal interrupted time series analyses were used to study TAVR utilization and difference-in-differences analyses were used to investigate post-TAVR readmissions. RESULTS: During the first year of payment reform (2014), TAVR utilization among Maryland Medicare beneficiaries dropped by 8% (95% confidence interval [CI]: -9.2% to -7.1%; p < 0.001), with no concomitant change in TAVR utilization in New Jersey (0.2%, 95% CI: 0%-1%, p = 0.09). Longitudinally, however, the All Payer Model did not impact TAVR utilization in Maryland compared to New Jersey. Difference-in-differences analyses demonstrated that implementation of the All Payer Model was not associated with significantly greater declines in 30-day post-TAVR readmissions in Maryland versus New Jersey (-2.1%; 95% CI: -5.2% to 0.9%; p =0.1). CONCLUSIONS: Maryland's All Payer Model resulted in an immediate decline in TAVR utilization, likely a result of hospitals adjusting to global budgeting. However, beyond this transition period, this cost-constrictive reform measure did not limit Maryland TAVR utilization. In addition, the All Payer Model did not reduce post-TAVR 30-day readmissions. These findings may help inform expansion of globally budgeted healthcare payment structures.

BRAF/MEK Inhibition as a Bridge to Immunotherapy for Symptomatic BRAF V600 Melanoma Brain Metastases: A Case Series.

Targeted and immune therapies have changed the paradigm of treatment for patients with metastatic melanoma. Treatment of patients with symptomatic melanoma brain metastases, however, is complicated by the frequent use of immune suppression for the management of vasogenic edema and the urgency in addressing disease burden. Use of BRAF/MEK inhibitors in patients with a corresponding BRAF V600 mutation often results in rapid response but is hindered by high rates of disease relapse and progression. Immunotherapy has higher durability of response, but the rate of response is slower and responses can be significantly diminished for patients on concurrent steroid therapy. Considering this gap in evidence-based guidance for optimal adjuvant therapy sequence in immunosuppressed patients with BRAF V600-mutant melanoma brain metastases, we report on 4 cases utilizing BRAF/MEK inhibitors as a bridging therapy for brain metastases management before initiation of immune checkpoint inhibitor therapy. Future prospective studies will be required to determine the optimal treatment sequencing for patients in this population with high unmet medical need.

Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency-Related Loss of Heterozygosity.

There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.

Analgesia and Sedation at Terminal Extubation: A Secondary Analysis From Death One Hour After Terminal Extubation Study Data.

OBJECTIVES: To describe the doses of opioids and benzodiazepines administered around the time of terminal extubation (TE) to children who died within 1 hour of TE and to identify their association with the time to death (TTD). DESIGN: Secondary analysis of data collected for the Death One Hour After Terminal Extubation study. SETTING: Nine U.S. hospitals. PATIENTS: Six hundred eighty patients between 0 and 21 years who died within 1 hour after TE (2010-2021). MEASUREMENTS AND MAIN RESULTS: Medications included total doses of opioids and benzodiazepines 24 hours before and 1 hour after TE. Correlations between drug doses and TTD in minutes were calculated, and multivariable linear regression performed to determine their association with TTD after adjusting for age, sex, last recorded oxygen saturation/F io2 ratio and Glasgow Coma Scale score, inotrope requirement in the last 24 hours, and use of muscle relaxants within 1 hour of TE. Median age of the study population was 2.1 years (interquartile range [IQR], 0.4-11.0 yr). The median TTD was 15 minutes (IQR, 8-23 min). Forty percent patients (278/680) received either opioids or benzodiazepines within 1 hour after TE, with the largest proportion receiving opioids only (23%, 159/680). Among patients who received medications, the median IV morphine equivalent within 1 hour after TE was 0.75 mg/kg/hr (IQR, 0.3-1.8 mg/kg/hr) ( n = 263), and median lorazepam equivalent was 0.22 mg/kg/hr (IQR, 0.11-0.44 mg/kg/hr) ( n = 118). The median morphine equivalent and lorazepam equivalent rates after TE were 7.5-fold and 22-fold greater than the median pre-extubation rates, respectively. No significant direct correlation was observed between either opioid or benzodiazepine doses before or after TE and TTD. After adjusting for confounding variables, regression analysis also failed to show any association between drug dose and TTD. CONCLUSIONS: Children after TE are often prescribed opioids and benzodiazepines. For patients dying within 1 hour of TE, TTD is not associated with the dose of medication administered as part of comfort care.

Current status and future potential of ex vivo lung perfusion in clinical lung transplantation.

Lung transplantation is accepted as a well-established and effective treatment for patients with end-stage lung disease. While the number of candidates added to the waitlist continues to rise, the number of transplants performed remains limited by the number of suitable organ donors. Ex vivo lung perfusion (EVLP) emerged as a method of addressing the organ shortage by allowing the evaluation and potential reconditioning of marginal donor lungs or minimizing risks of prolonged ischemic time due to logistical challenges. The currently available FDA-approved EVLP systems have demonstrated excellent outcomes in clinical trials, and retrospective studies have demonstrated similar post-transplant survival between recipients who received marginal donor lungs perfused using EVLP and recipients who received standard criteria lungs stored using conventional methods. Despite this, widespread utilization has plateaued in the last few years, likely due to the significant costs associated with initiating EVLP programs. Centralized, dedicated EVLP perfusion centers are currently being investigated as a potential method of further expanding utilization of this technology. In the preclinical setting, potential applications of EVLP that are currently being studied include prolongation of organ preservation, reconditioning of unsuitable lungs, and further enhancement of already suitable lungs. As adoption of EVLP technology becomes more widespread, we may begin to see future implementation of these potential applications into the clinical setting.

Expanding the Criteria for Heart Transplantation Donors: A Review of DCD, Increased Ischemic Times, HCV, HIV, and Extended Criteria Donors.

With the demand for heart transplantation continuing to outpace the available donor organs, previously underutilized donors are now being reconsidered. We sought to describe the emerging techniques and outcomes of expanded criteria heart transplantation. A comprehensive review of the recent literature concerning expanded donor selection in heart transplantation was performed using the PubMed MEDLINE database. To characterize trends in transplant practice, the United Network for Organ Sharing (UNOS/OPTN) registry was queried for all adult isolated heart transplants since 2010, and data regarding transplant parameters was collected. Donation after cardiac death (DCD), DCD with normothermic regional perfusion, increased ischemic time, hepatitis C positive donor organs, HIV-positive donor organs, and extended criteria donors were identified as promising avenues currently being explored to expand the number of donor organs. The utilization of various expanded criteria for heart transplantation was summarized since 2010 and showed an increasing use of these donor organs, contributing to the overall increasing frequency of heart transplantation. Utilization of expanded criteria for donor selection in heart transplantation has the potential to increase the supply of donor organs with comparable outcomes in selected recipients.

Costs and Readmissions Associated with Type A Aortic Dissections at High- and Low-Volume Centers.

BACKGROUND: Costs and readmissions associated with type A aortic dissection repairs are not well understood. We investigated statewide readmissions, costs, and outcomes associated with the surgical management of type A aortic dissection repairs at low- and high-volume centers. METHODS: We identified all adult type A aortic dissection patients who underwent operative repair in the Maryland Health Services Cost Review Commission's database (2012-2020). Hospitals were stratified into high- (top quartile of total repairs) or low-volume centers. RESULTS: Of the 249 patients included, 193 (77.5%) were treated at a high-volume center. Patients treated at high- and low-volume centers had no differences in age, sex, race, primary payer, or severity (all p > 0.5). High- compared to low-volume centers had a greater proportion of patients transferred in (71.5% vs. 17.9%, p < 0.001). High-volume centers also had longer lengths of stay (12 vs. 8 days, p < 0.001), similar inpatient mortality (13.0% vs. 16.1%, p = 0.6), and similar proportion of patients readmitted (54.9% vs. 51.8%, p = 0.7). High-volume centers had greater index admission costs ($114,859 vs. $72,090, p < 0.001) and similar readmission costs ($48,367 vs. $42,204, p = 0.5). At high-volume centers, transferred patients compared to direct admissions had greater severity of illness (p = 0.05), similar mortality (p = 0.53), and greater lengths of stay (p = 0.05). CONCLUSIONS: High-volume centers had a greater number of patients transferred from other institutions compared to low-volume centers. High-volume centers were associated with increased index admission resource utilization, with transfer patients having higher illness severity and greater resource utilization, yet similar mortality, compared to direct admission patients.

Homologous Recombination Deficiency (HRD) in Cutaneous Oncology.

Skin cancers, including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and melanoma, are the most common malignancies in the United States. Loss of DNA repair pathways in the skin plays a significant role in tumorigenesis. In recent years, targeting DNA repair pathways, particularly homologous recombination deficiency (HRD), has emerged as a potential therapeutic approach in cutaneous malignancies. This review provides an overview of DNA damage and repair pathways, with a focus on HRD, and discusses major advances in targeting these pathways in skin cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to exploit HRD in cancer cells. PARP inhibitors disrupt DNA repair mechanisms by inhibiting PARP enzymatic activity, leading to the accumulation of DNA damage and cell death. The concept of synthetic lethality has been demonstrated in HR-deficient cells, such as those with BRCA1/2 mutations, which exhibit increased sensitivity to PARP inhibitors. HRD assessment methods, including genomic scars, RAD51 foci formation, functional assays, and BRCA1/2 mutation analysis, are discussed as tools for identifying patients who may benefit from PARP inhibitor therapy. Furthermore, HRD has been implicated in the response to immunotherapy, and the combination of PARP inhibitors with immunotherapy has shown promising results. The frequency of HRD in melanoma ranges from 18% to 57%, and studies investigating the use of PARP inhibitors as monotherapy in melanoma are limited. Further research is warranted to explore the potential of PARP inhibition in melanoma treatment.

Prostatic Artery Embolization Versus Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia: A Cost-Effectiveness Analysis.

PURPOSE: To compare the cost effectiveness of prostatic artery embolization (PAE) with that of transurethral resection of the prostate (TURP) for the treatment of medically refractory benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A cost-effectiveness analysis with Markov modeling was performed, comparing the clinical course after PAE with that after TURP for 3 years. Probabilities were obtained from the available literature, and costs were based on Medicare reimbursements and published cost analyses. Outcomes were measured using quality-adjusted life-year (QALY). Statistical analyses included base case calculation, probabilistic sensitivity analysis, and deterministic sensitivity analysis to assess the robustness of the conclusion under different clinical scenarios. RESULTS: Base case calculation showed comparable outcomes (PAE, 2.845 QALY; TURP, 2.854 QALY), with a cost difference of $3,104 (PAE, $2,934; TURP, $6,038). The incremental cost-effectiveness ratio was $360,249/QALY. PAE was dominant in 23.2% and more cost effective in 48.4% of the probabilistic sensitivity analysis simulations. PAE was better if its recurrence risk was <20.4% per year and even when the TURP recurrence risk was assumed to be 0%. TURP would be more cost effective when its procedural cost was <$3,367 or the PAE procedural cost >$4,409. PAE remained cost effective when varying the risks and costs of the minor and major short-term or long-term adverse events of both procedures. TURP would be the better strategy if the utility of BPH recurrence was <0.85 QALY. CONCLUSIONS: PAE is a cost-effective strategy to treat medically refractory BPH, resulting in comparable health benefits at a lower cost than that of TURP even when accounting for extreme alterations in adverse events, costs, and recurrence rates.

Massive left atrial thrombus evades multimodality imaging as a myxoma in a bicaval heart transplant recipient.

Intracardiac masses are an extremely rare and poorly described complication following a bicaval heart transplantation. We describe the case of an asymptomatic 62-year-old male with a large left atrial mass found incidentally on transthoracic echocardiography 6 years post-transplant. A battery of additional imaging tests was ordered including transesophageal echocardiography, 18 F-fluorodeoxyglucose positron emission tomography/computed tomography, and T1 and T2 magnetic resonance imaging. Although imaging biomarkers were generally nonspecific, the mass was most consistent with a cardiac myxoma. However, intraoperative findings confirmed by pathology revealed a massive organizing thrombus. The patient had an uneventful recovery after surgical removal of the mass. Our case highlights a very rare phenomenon in heart transplant recipients which remains a unique diagnostic challenge even with current advances in imaging.

Multiple environmental parameters impact lipid cyclization in Sulfolobus acidocaldarius.

Adaptation of lipid membrane composition is an important component of archaeal homeostatic response. Historically, the number of cyclopentyl and cyclohexyl rings in the glycerol dibiphytanyl glycerol tetraether (GDGT) Archaeal lipids has been linked to variation in environmental temperature. However, recent work with GDGT-making archaea highlight the roles of other factors, such as pH or energy availability, in influencing the degree of GDGT cyclization. To better understand the role of multiple variables in a consistent experimental framework and organism, we cultivated the model Crenarchaeon Sulfolobus acidocaldarius DSM639 at different combinations of temperature, pH, oxygen flux, or agitation speed. We quantified responses in growth rate, biomass yield, and core lipid compositions, specifically the degree of core GDGT cyclization. The degree of GDGT cyclization correlated with growth rate under most conditions. The results suggest the degree of cyclization in archaeal lipids records a universal response to energy availability at the cellular level, both in thermoacidophiles, and in other recent findings in the mesoneutrophilic Thaumarchaea. Although we isolated the effects of key individual parameters, there remains a need for multi-factor experiments (e.g., pH + temperature + redox) in order to more robustly establish a framework to better understand homeostatic membrane responses.

Energy flux controls tetraether lipid cyclization in Sulfolobus acidocaldarius.

Microorganisms regulate the composition of their membranes in response to environmental cues. Many Archaea maintain the fluidity and permeability of their membranes by adjusting the number of cyclic moieties within the cores of their glycerol dibiphytanyl glycerol tetraether (GDGT) lipids. Cyclized GDGTs increase membrane packing and stability, which has been shown to help cells survive shifts in temperature and pH. However, the extent of this cyclization also varies with growth phase and electron acceptor or donor limitation. These observations indicate a relationship between energy metabolism and membrane composition. Here we show that the average degree of GDGT cyclization increases with doubling time in continuous cultures of the thermoacidophile Sulfolobus acidocaldarius (DSM 639). This is consistent with the behavior of a mesoneutrophile, Nitrosopumilus maritimus SCM1. Together, these results demonstrate that archaeal GDGT distributions can shift in response to electron donor flux and energy availability, independent of pH or temperature. Paleoenvironmental reconstructions based on GDGTs thus capture the energy available to microbes, which encompasses fluctuations in temperature and pH, as well as electron donor and acceptor availability. The ability of Archaea to adjust membrane composition and packing may be an important strategy that enables survival during episodes of energy stress.

Percutaneous Cryoablation for Stage 1 Renal Cell Carcinoma: Outcomes from a 10-year Prospective Study and Comparison with Matched Cohorts from the National Cancer Database.

Background Percutaneous cryoablation (PCA) is an increasingly utilized treatment for stage I renal cell carcinoma (RCC), albeit without supportive level I evidence. Purpose Primary objective was to determine the 10-year oncologic outcomes of PCA for stage I RCC in a prospective manner. Secondary objectives were to compare outcomes after partial nephrectomy (PN) and radical nephrectomy (RN) from the National Cancer Database (NCDB), to determine long-term renal function, and to determine the risk of metachronous disease. Materials and Methods In this institutional review board-approved prospective observational study (2006-2013), study participants with single, sporadic, biopsy-proven RCC were included to calculate the 10-year overall survival, recurrence-free survival, and disease-specific survival after PCA. Results were compared with matched PN and RN NCDB cohorts. Overall and recurrence-free survival probabilities were estimated by using nonparametric maximum likelihood estimator. Disease-specific survival was estimated by using the redistribution-to-right method. Age at diagnosis was stratified as a risk for survival. The effect on estimated glomerular filtration rate, serum creatinine level, and the risk for hemodialysis and metachronous disease were calculated. Results One hundred thirty-four patients (46% men) with single, sporadic, biopsy-proven RCC (median size ± standard deviation, 2.8 cm ± 1.4) were included. Overall survival was 86% (95% confidence interval [CI]: 80%, 93%) and 72% (95% CI: 62%, 83%), recurrence-free survival was 85% (95% CI: 79%, 91%) and 69% (95% CI: 59%, 79%) (improved over surgery), and disease-specific survival was 94% (95% CI: 90%, 98%) at both 5 years and 10 years (similar to surgery), respectively. The 10-year risk of hemodialysis was 2.3%. Risk of metachronous RCC was 6%. Charlson/Deyo Combined Comorbidity score analysis showed decreasing overall survival with increasing comorbidity index. The PCA cohort outperformed both RN- and PN-matched subgroups in all Charlson/Deyo Combined Comorbidity score categories. Conclusion Percutaneous cryoablation yielded a 10-year disease-specific survival of 94%, equivalent to that reported after radical or partial nephrectomy. Overall survival probability after percutaneous cryoablation at 5 years and 10 years was longer than for radical or partial nephrectomy, especially for patients at higher risk (Charlson/Deyo Combined Comorbidity score ≥2). © RSNA, 2020.

Correlates of response and outcomes with talimogene laherperpvec.

BACKGROUND AND OBJECTIVES: Patients with in-transit or limited cutaneous metastatic melanoma may benefit from intralesional injections with talimogene laherparepvec (TVEC), a modified oncolytic herpesvirus. However, its use in patients with adverse prognostic scores in a real-life clinical setting has not been studied. METHODS: We performed a two-center retrospective analysis of 40 patients with metastatic melanoma treated with TVEC from 2015-2017. Demographics, overall response, and survival after therapy were noted. RESULTS: Overall, there was a durable response rate of 40%; median progression-free survival (PFS) was 10.5 months and median overall survival (OS) was not reached. Bulky disease was associated with decreased OS (15.7 months vs not reached, P < .05) and mPFS (2.3 months vs not reached, P < .05), when compared with smaller tumors. Poor performance status (ECOG 2-3) was associated with worse OS (10.2 months vs not reached, P < .05) and PFS (2.1 months vs not reached, P < .05) compared to patients with ECOG 0-1. There was no difference in the outcomes with age greater than 75 or with prior therapies. Adverse events were relatively tolerable. CONCLUSIONS: These findings demonstrate that TVEC is an effective and safe treatment for metastatic melanoma in a real-life clinical setting, and suggest parameters to aid in appropriate therapy selection for optimal response.