Is PSMA PET/CT cost-effective for the primary staging in prostate cancer? First results for European countries and the USA based on the proPSMA trial.

PURPOSE: The proPSMA trial at ten Australian centers demonstrated increased sensitivity and specificity for PSMA PET/CT compared to conventional imaging regarding metastatic status in primary high-risk prostate cancer patients. A cost-effectiveness analysis showed benefits of PSMA PET/CT over conventional imaging for the Australian setting. However, comparable data for other countries are lacking. Therefore, we aimed to verify the cost-effectiveness of PSMA PET/CT in several European countries as well as the USA. METHODS: Clinical data on diagnostic accuracy were derived from the proPSMA trial. Costs for PSMA PET/CT and conventional imaging were taken from reimbursements of national health systems and individual billing information of selected centers in Belgium, Germany, Italy, the Netherlands, and the USA. For comparability, scan duration and the decision tree of the analysis were adopted from the Australian cost-effectiveness study. RESULTS: In contrast to the Australian setting, PSMA PET/CT was primarily associated with increased costs in the studied centers in Europe and the USA. Mainly, the scan duration had an impact on the cost-effectiveness. However, costs for an accurate diagnosis using PSMA PET/CT seemed reasonably low compared to the potential consequential costs of an inaccurate diagnosis. CONCLUSION: We assume that the use of PSMA PET/CT is appropriate from a health economic perspective, but this will need to be verified by a prospective evaluation of patients at initial diagnosis.

Impact of Telemedicine on Extended Focused Assessment With Sonography for Trauma Performance and Workload by Critical Care Transport Personnel.

INTRODUCTION: There are currently no reports on whether telementoring for extended focused assessment with sonography for trauma (eFAST) improves critical care transport providers' performance in prehospital settings. Our objective was to determine the impact of teleguidance on eFAST performance and quantify workload experience. METHODS: Eight trauma injury modules were selected on simulated patients. Critical care transport (CCT) providers were tasked to complete one independent and one emergency physician-telementored eFAST. The time to completion and the percent of correct findings were obtained. Participants completed the NASA Task Load Index after each iteration to assess workload. RESULTS: Eight independent and 8 telementored eFASTs were completed. The mean times to complete the independent and telementored eFAST were 5 minutes 16 seconds (95% confidence interval [CI], 3 minutes 32 seconds, 6 minutes 59 seconds) and 8 minutes 27 seconds (95% CI, 5 minutes 14 seconds, 11 minutes 39 seconds), respectively (P = .06). The percentage of correctly identified injuries for the independent versus the teleguided eFAST was 65% versus 92.5% (P = .01). The CCT providers experienced higher mental (P = .004), temporal (P = .01), and effort (P = .004) demands; greater frustration (P = .001); and subjective lower performance (P = .003) during independent trials. The emergency physician experienced higher mental (P = .001), temporal (P = .02), effort (P = .005), and frustration (P = .001) demands than the CCT members. CONCLUSION: The teleguided eFAST yielded higher accuracy than the independent eFAST. The CCT providers relied on teleguidance of the remote physician when performing the eFAST. Teleguidance may improve the accuracy of ultrasounds performed by prehospital personnel in real-life scenarios.

Cost-Effectiveness Analysis of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer poses a therapeutic challenge with poor prognosis. The VISION trial showed prolonged progression-free and overall survival in patients treated with lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) radioligand therapy compared with using the standard of care (SoC) alone. The objective of this study was to determine the cost-effectiveness of 177Lu-PSMA-617 treatment compared with SoC therapy. METHODS: A partitioned survival model was developed using data from the VISION trial, which included overall and progression-free survival and treatment regimens for 177Lu-PSMA-617 and SoC. Treatment costs, utilities for health states, and adverse events were derived from public databases and the literature. Because 177Lu-PSMA-617 was only recently approved, costs for treatment were extrapolated from 177Lu-DOTATATE. Outcome measurements included the incremental cost, effectiveness, and cost-effectiveness ratio. The analysis was performed in a US setting from a healthcare system perspective over the lifetime horizon of 60 months. The willingness-to-pay threshold was set to $50,000, $100,000, and $200,000 per quality-adjusted life years (QALYs). RESULTS: The 177Lu-PSMA-617 group was estimated to gain 0.42 incremental QALYs. Treatment using 177Lu-PSMA-617 led to an increase in costs compared with SoC ($169,110 vs $85,398). The incremental cost, effectiveness, and cost-effectiveness ratio for 177Lu-PSMA-617 therapy was $200,708/QALYs. Sensitivity analysis showed robustness of the model regarding various parameters, which remained cost-effective at all lower and upper parameter bounds. In probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, therapy using 177Lu-PSMA-617 was determined as the cost-effective strategy in 37.14% of all iterations at a willingness-to-pay threshold of $200,000/QALYs. CONCLUSIONS: Treatment using 177Lu-PSMA-617 was estimated to add a notable clinical benefit over SoC alone. Based on the model results, radioligand therapy represents a treatment strategy for patients with metastatic castration-resistant prostate cancer with cost-effectiveness in certain scenarios.

Feasibility and Acceptance of a Teletrauma Surgery Consult Service to Rural and Community Hospitals: A Pilot Study.

BACKGROUND: Many trauma patients currently transferred from rural and community hospitals (RCH) to Level I trauma centers (LITC) for trauma surgery evaluation may instead be appropriate for immediate discharge or admission to the local facility after evaluation by a trauma and acute care surgery (TACS) surgeon. Unnecessary use of resources occurs with current practice. We aimed to demonstrate the feasibility and acceptance of a teletrauma surgery consultation service between LITC and RCH. STUDY DESIGN: LITC TACS surgeons provided telehealth consults on trauma patients from 3 local RCHs. After consultation, appropriate patients were transferred to LITC; selected patients remained at or were discharged from RCH. Participating TACS surgeons and RCH physicians were surveyed. RESULTS: A total of 28 patients met inclusion criteria during the 5-month pilot phase, with 7 excluded due to workflow issues. The mean ± SD age was 63 ± 17 years. Of 21 patients, 7 had intracranial hemorrhage; 12 had rib fractures. The mean ± SD Injury Severity Score was 8.1 ± 4.0). A total of 6 patients were discharged from RCH, 4 admitted to RCH hospitalist service, 2 transferred to a LITC emergency room, and 9 transferred to LITC as direct admission. There was one 30-day readmission and no missed injuries or complications, or deaths. RCH providers were highly satisfied with the teletrauma surgery consultation service, TACS surgeons, and equipment used. Mental demand and effort of consulting TACS surgeons decreased significantly as the consult number increased. CONCLUSIONS: Teletrauma surgery consultation involving 3 RCH within our system is feasible and acceptable. A total of 10 transfers and 19 emergency department visits were avoided. There was favorable acceptance by RCH providers and TACS surgeons.

Characterization of the Gateway Decarboxylase for Psilocybin Biosynthesis.

The l-tryptophan decarboxylase PsiD catalyzes the initial step of the metabolic cascade to psilocybin, the major indoleethylamine natural product of the "magic" mushrooms and a candidate drug against major depressive disorder. Unlike numerous pyridoxal phosphate (PLP)-dependent decarboxylases for natural product biosyntheses, PsiD is PLP-independent and resembles type II phosphatidylserine decarboxylases. Here, we report on the in vitro biochemical characterization of Psilocybe cubensis PsiD along with in silico modeling of the PsiD structure. A non-canonical serine protease triad for autocatalytic cleavage of the pro-protein was predicted and experimentally verified by site-directed mutagenesis.

Spatial Volume Necessary to Perform Open Appendectomy in a Spacecraft.

BACKGROUND: With the increase in crewed commercial spaceflight and expeditions to the Moon and Mars, the risk of critical surgical problems and need for procedures increases. Appendicitis and appendectomy are the most common surgical pathology and procedure performed, respectively. The habitable volume of current spacecraft ranges from 4 m³ (Soyuz) to 425 m³ (International Space Station). We investigated the minimum volume required to perform an appendectomy and compared that to habitable spacecraft volumes.METHODS: The axes of a simulated operating room were marked and cameras placed to capture movements. An expert surgeon, chief surgical resident, junior surgical resident, and a nonsurgeon physician each performed a Focused Assessment with Sonography for Trauma and an appendectomy on a simulated patient. Dimensions and volume needed were collected and compared using unpaired t-tests.RESULTS: Mean volume (± SD) needed was 3.83 m³ ± 0.47 m³ for standing and 3.68 m³ ± 0.49 m³ for kneeling (P = 0.638). Minimal volume needed was 3.20 m³ for standing and 3.26 m³ for kneeling. Minimal theoretical volume was 2.99 m³ for standing and 2.87 m³ for kneeling.DISCUSSION: The unencumbered volume needed for an appendectomy is between 2.87 m³ and 4.3 m³. It may be technically feasible to perform an open appendectomy inside the smallest of currently operating spacecraft, at 4 m³ (Soyuz-MS). Space vessels operating without rapid evacuation to Earth will need to consider this volume for potential surgical emergencies. Additional investigation on microgravity and standardization of procedures for novices must be completed.Kamine TH, Siu M, Kramer K, Kelly E, Alouidor R, Fernandez G, Levin D. Spatial volume necessary to perform open appendectomy in a spacecraft. Aerosp Med Hum Perform. 2022; 93(10):760-763.

From LUVs to GUVs─How to Cover Micrometer-Sized Pores with Membranes.

Pore-spanning membranes (PSMs) are a versatile tool to investigate membrane-confined processes in a bottom-up approach. Pore sizes in the micrometer range are most suited to visualize PSMs using fluorescence microscopy. However, the preparation of these PSMs relies on the spreading of giant unilamellar vesicles (GUVs). GUV production faces several limitations. Thus, alternative ways to generate PSMs starting from large or small unilamellar vesicles that are more reproducibly prepared are highly desirable. Here we describe a method to produce PSMs obtained from large unilamellar vesicles, making use of droplet-stabilized GUVs generated in a microfluidic device. We analyzed the lipid diffusion in the free-standing and supported parts of the PSMs using z-scan fluorescence correlation spectroscopy and fluorescence recovery after photobleaching experiments in combination with finite element simulations. Employing atomic force indentation experiments, we also investigated the mechanical properties of the PSMs. Both lipid diffusion constants and lateral membrane tension were compared to those obtained on PSMs derived from electroformed GUVs, which are known to be solvent- and detergent-free, under otherwise identical conditions. Our results demonstrate that the lipid diffusion, as well as the mechanical properties of the resulting PSMs, is almost unaffected by the GUV formation procedure but depends on the chosen substrate functionalization. With the new method in hand, we were able to reconstitute the syntaxin-1A transmembrane domain in microfluidic GUVs and PSMs, which was visualized by fluorescence microscopy.

Time Cost of Provider Skill: A Pilot Study of Medical Officer Occupied Time By Knowledge, Skill, and Ability Level.

INTRODUCTION: On space missions one must consider the operating cost of the medical system on crew time. Medical Officer Occupied Time (MOOT) may vary significantly depending on provider skill. This pilot study assessed the MOOT Skill Effect (MOOTSkE).METHODS: An expert surgeon (ES), fifth year surgical resident (PGY5), second year surgical resident (PGY2), and an expert Emergency Physician (EP) with only 4 mo direct surgical training each performed two simulated appendectomies. The completion times for endotracheal intubation, appendectomy, and two subprocedures (multilayer tissue repair and single layer tissue repair) were recorded.RESULTS: The ES performed the appendectomy in 410 s, the PGY-5 in 498 s, the PGY-2 in 645 s, and the EP in 973 s on average. The PGY-2 and EP time difference was significant compared to the expert. The PGY-5 was not. The EP's time was significantly longer for the appendectomy and the multilayer repair than either surgical resident. For the single layer repair, only the EP-ES difference was significant. A single intubation attempt by the PGY-2 took 73 s while the EP averaged 27 s. The average recorded MOOTSkE between novice and expert was 2.5 (SD 0.34).DISCUSSION: This pilot study demonstrates MOOTSkE can be captured using simulated procedures. It showed the magnitude of the MOOTSkE is likely substantial, suggesting that a more highly trained provider may save substantial crew time. Limitations included small sample size, limited number of procedures, a simulation that may not reflect real world conditions, and suboptimal camera angles.Levin DR, Siu M, Kramer K, Kelly E, Alouidor R, Fernandez G, Kamine T. Time cost of provider skill: a pilot study of medical officer occupied time by knowledge, skill, and ability level. Aerosp Med Hum Perform. 2022; 93(11):816-821.

Optimal Timing of Cholecystectomy for Acute Cholecystitis: A Retrospective Cohort Study.

Background Laparoscopic cholecystectomy performed less than 72 hours from hospital admission for acute cholecystitis has shown to decrease hospital cost without an increase in length of stay (LOS). Very few studies have examined clinical and cost outcomes of performing cholecystectomy less than 24 hours from hospital admission. The aim of this study was to examine the cost and LOS of laparoscopic cholecystectomy performed on an early (less than 24 hours from admission) and late (more than 24 hours from hospital admission) basis. Methods We performed a retrospective observational study of 569 patients at Baystate Medical Center, Springfield, USA, who underwent urgent laparoscopic cholecystectomy for acute cholecystitis between January 1, 2018 and February 28, 2020. We evaluated preoperative/postoperative LOS, operative duration, hospital cost, and patient complications. Results 468 patients underwent urgent laparoscopic cholecystectomy for acute cholecystitis during our study period. Early cholecystectomy (less than 24 hours from admission) had an overall decreased LOS (43.6 hours versus 102.9 hours, p-value < 0.01) and decreased hospital cost ($23,736.70 versus $30,176.40, p-value < 0.01) compared to late cholecystectomy (more than 24 hours from admission). There was also a significantly higher rate of bile leak in patients who underwent surgery more than 24 hours from hospital admission compared to those who had surgery less than 24 hours from admission (5.9% versus 0.4%, p-value < 0.01). Additionally, those procedures performed greater than 24 hours from hospital admission were significantly more likely to be converted to an open procedure (6.9% versus 2.2%, p-value = 0.02).  Conclusion Urgent laparoscopic cholecystectomy performed within 24 hours of hospital admission for acute cholecystitis decreased hospital cost, LOS, and operative complications in our institution's patient population. Our data suggests that performing laparoscopic cholecystectomy within 24 hours of hospital admission would be beneficial from a patient and hospital standpoint.

American Helicopter Emergency Medical Service Pilots Report to Work Despite High Rates of Sleepiness.

OBJECTIVE: Previous studies on helicopter emergency medical service (HEMS) pilots found a positive correlation among fatigue, nodding off in flight, and accidents. We sought to quantify the amount of sleepiness in HEMS pilots using the Epworth Sleepiness Scale (ESS). METHODS: An anonymous survey was sent via the National EMS Pilots Association emergency medical services listserv including demographics, the ESS, and subjective effects of fatigue on flying. Statistical analyses were performed using the t-test and analysis of variance. RESULTS: Thirty-one surveys were returned. Twenty-one (65%) reported an ESS > 10, indicating excessive daytime sleepiness. Twelve (39%) reported nodding off in flight; 20 (65%) indicated that they should have refused to fly, but only 14 (45%) actually did. En route was the most likely phase of flight to be affected by fatigue (23 [74%]), whereas takeoff (2 [7%]) and landing (2 [7%]) were the least likely to be affected. CONCLUSION: Many HEMS pilots in this small study reported excessive daytime sleepiness. Most respondents indicated that they should have turned down a flight because of fatigue. More research is necessary to quantify the burden of fatigue among HEMS pilots.

A Western Massachusetts hospital system's response to the COVID-19 pandemic.

OBJECTIVE: The objective of this paper was to outline a novel model created for the management of the critical care surge due to coronavirus disease 2019 (COVID-19) in a Western Massachusetts hospital. SETTING: This model was created and implemented at a Western Massachusetts Level 1 Trauma and tertiary referral center. CONCLUSIONS: This article outlines a model devised by an interdisciplinary team for rapid expansion of critical care services by increasing allocated space, staffing, and supplies via modifications of existing systems of care to accommodate a predicted large critical care patient surge due to the COVID-19 pandemic. We predict that this model can be utilized and adapted for future critical care surges in times of similar pandemic situations.

Surviving traumatic cardiac arrest: Identification of factors associated with survival.

INTRODUCTION: The endpoint of resuscitative interventions after traumatic injury resulting in cardiopulmonary arrest varies across institutions and even among providers. The purpose of this study was to examine survival characteristics in patients suffering torso trauma with no recorded vital signs (VS) in the emergency department (ED). METHODS: The National Trauma Data Bank was analyzed from 2007 to 2015. Inclusion criteria were patients with blunt and penetrating torso trauma without VS in the ED. Patients with head injuries, transfers from other hospitals, or those with missing values were excluded. The characteristics of survivors were evaluated, and statistical analyses performed. RESULTS: A total of 24,191 torso trauma patients without VS were evaluated in the ED and 96.6% were declared dead upon arrival. There were 246 survivors (1%), and 73 (0.3%) were eventually discharged home. Of patients who responded to resuscitation (812), the survival rate was 30.3%. Injury severity score (ISS), penetrating mechanism (odds ratio [OR] 1.99), definitive chest (OR 1.59) and abdominal surgery (OR 1.49) were associated with improved survival. Discharge to home (or police custody) was associated with lower ISS (OR 0.975) and shorter ED time (OR 0.99). CONCLUSION: Over a recent nine-year period in the United States, nearly 25,000 trauma patients were treated at trauma centers despite lack of VS. Of these patients, only 73 were discharged home. A trauma center would have to attempt over one hundred resuscitations of traumatic arrests to save one patient, confirming previous reports that highlight a grave prognosis. This creates a dilemma in treatment for front line workers and physicians with resource utilization and consideration of safety of exposure, particularly in the face of COVID-19.

Right hospital, right patients: Penetrating injury patients treated at high-volume penetrating trauma centers have lower mortality.

BACKGROUND: The recognition of the relationship between volume and outcomes led to the regionalization of trauma care. The relationship between trauma mechanism-subtype and outcomes has yet to be explored. We hypothesized that trauma centers with a high volume of penetrating trauma patients might be associated with a higher survival rate for penetrating trauma patients. METHODS: A retrospective cohort analysis of penetrating trauma patients presenting between 2011 and 2015 was conducted using the National Trauma Database and the trauma registry at the Stroger Cook County Hospital. Linear regression was used to determine the relationship between mortality and the annual volume of penetrating trauma seen by the treating hospital. RESULTS: Nationally, penetrating injuries account for 9.5% of the trauma cases treated. Patients treated within the top quartile penetrating-volume hospitals (≥167 penetrating cases per annum) are more severely injured (Injury Severity Score: 8.9 vs. 7.7) than those treated at the lowest quartile penetrating volume centers (<36.6 patients per annum). There was a lower mortality rate at institutions that treated high numbers of penetrating trauma patients per annum. A penetrating trauma mortality risk adjustment model showed that the volume of penetrating trauma patients was an independent factor associated with survival rate. CONCLUSION: Trauma centers with high penetrating trauma patient volumes are associated with improved survival of these patients. This association with improved survival does not hold true for the total trauma volume at a center but is specific to the volume of the penetrating trauma subtype. LEVEL OF EVIDENCE: Prognostic/Epidemiology Study, Level-III; Therapeutic/Care Management, Level IV.

Quantification of Hv1-induced proton translocation by a lipid-coupled Oregon Green 488-based assay.

Passive proton translocation across membranes through proton channels is generally measured with assays that allow a qualitative detection of the H+-transfer. However, if a quantitative and time-resolved analysis is required, new methods have to be developed. Here, we report on the quantification of pH changes induced by the voltage-dependent proton channel Hv1 using the commercially available pH-sensitive fluorophore Oregon Green 488-DHPE (OG488-DHPE). We successfully expressed and isolated Hv1 from Escherichia coli and reconstituted the protein in large unilamellar vesicles. Reconstitution was verified by surface enhanced infrared absorption (SEIRA) spectroscopy and proton activity was measured by a standard 9-amino-6-chloro-2-methoxyacridine assay. The quantitative OG488-DHPE assay demonstrated that the proton translocation rate of reconstituted Hv1 is much smaller than those reported in cellular systems. The OG488-DHPE assay further enabled us to quantify the KD-value of the Hv1-inhibitor 2-guanidinobenzimidazole, which matches well with that found in cellular experiments. Our results clearly demonstrate the applicability of the developed in vitro assay to measure proton translocation in a quantitative fashion; the assay allows to screen for new inhibitors and to determine their characteristic parameters. Graphical abstract ᅟ.

Isoprenylcysteine carboxyl methyltransferase activity modulates endothelial cell apoptosis.

Extracellular ATP, adenosine (Ado), and adenosine plus homocysteine (Ado/HC) cause apoptosis of cultured pulmonary artery endothelial cells through the enhanced formation of intracellular S-adenosylhomocysteine and disruption of focal adhesion complexes. Because an increased intracellular ratio of S-adenosylhomocysteine/S-adenosylmethionine favors inhibition of methylation, we hypothesized that Ado/HC might act by inhibition of isoprenylcysteine-O-carboxyl methyltransferase (ICMT). We found that N-acetyl-S-geranylgeranyl-L-cysteine (AGGC) and N-acetyl-S-farnesyl-L-cysteine (AFC), which inhibit ICMT by competing with endogenous substrates for methylation, caused apoptosis. Transient overexpression of ICMT inhibited apoptosis caused by Ado/HC, UV light exposure, or tumor necrosis factor-alpha. Because the small GTPase, Ras, is a substrate for ICMT and may modulate apoptosis, we also hypothesized that inhibition of ICMT with Ado/HC or AGGC might cause endothelial apoptosis by altering Ras activation. We found that ICMT inhibition decreased Ras methylation and activity and the activation of the downstream signaling molecules Akt, ERK-1, and ERK-2. Furthermore, overexpression of wild-type or dominant active H-Ras blocked Ado/HC-induced apoptosis. These findings suggest that inhibition of ICMT causes endothelial cell apoptosis by attenuation of Ras GTPase methylation and activation and its downstream antiapoptotic signaling pathway.