Bilateral phrenic nerve block to reduce hazardous respiratory drive in a mechanically ventilated patient with COVID-19-A case report.

Key Clinical Message: Forced inspiration during mechanical ventilation risks self-inflicted lung injury. However, controlling it with sedation or paralysis may cause polyneuropathy and myopathy. We tested bilateral phrenic nerve paralysis with local anesthetic in a patient, showing reduced inspiratory force. This offers an alternative to drug-induced muscle paralysis. Abstract: Mechanical ventilation, although a life-saving measure, can also pose a risk of causing lung injury known as "ventilator-induced lung injury" or VILI. Patients undergoing mechanical ventilation sometimes exhibit heightened inspiratory efforts, wherein the negative pressure generated by the respiratory muscles adds to the positive pressure generated by the ventilator. This combination of high pressures can lead to a syndrome similar to VILI, referred to as "patient self-inflicted lung injury" or P-SILI. Prevention of P-SILI requires the administration of deep sedation and muscle paralysis to the patients, but both these measures can have undesired effects on their health. In this case report, we demonstrate the effect of a bilateral phrenic nerve block aiming to reduce excessive inspiratory respiratory efforts in a patient suffering from COVID-19 pneumonitis.

Mechanisms maintaining right ventricular contractility-to-pulmonary arterial elastance ratio in VA ECMO: a retrospective animal data analysis of RV-PA coupling.

BACKGROUND: To optimize right ventricular-pulmonary coupling during veno-arterial (VA) ECMO weaning, inotropes, vasopressors and/or vasodilators are used to change right ventricular (RV) function (contractility) and pulmonary artery (PA) elastance (afterload). RV-PA coupling is the ratio between right ventricular contractility and pulmonary vascular elastance and as such, is a measure of optimized crosstalk between ventricle and vasculature. Little is known about the physiology of RV-PA coupling during VA ECMO. This study describes adaptive mechanisms for maintaining RV-PA coupling resulting from changing pre- and afterload conditions in VA ECMO. METHODS: In 13 pigs, extracorporeal flow was reduced from 4 to 1 L/min at baseline and increased afterload (pulmonary embolism and hypoxic vasoconstriction). Pressure and flow signals estimated right ventricular end-systolic elastance and pulmonary arterial elastance. Linear mixed-effect models estimated the association between conditions and elastance. RESULTS: At no extracorporeal flow, end-systolic elastance increased from 0.83 [0.66 to 1.00] mmHg/mL at baseline by 0.44 [0.29 to 0.59] mmHg/mL with pulmonary embolism and by 1.36 [1.21 to 1.51] mmHg/mL with hypoxic pulmonary vasoconstriction (p < 0.001). Pulmonary arterial elastance increased from 0.39 [0.30 to 0.49] mmHg/mL at baseline by 0.36 [0.27 to 0.44] mmHg/mL with pulmonary embolism and by 0.75 [0.67 to 0.84] mmHg/mL with hypoxic pulmonary vasoconstriction (p < 0.001). Coupling remained unchanged (2.1 [1.8 to 2.3] mmHg/mL at baseline; - 0.1 [- 0.3 to 0.1] mmHg/mL increase with pulmonary embolism; - 0.2 [- 0.4 to 0.0] mmHg/mL with hypoxic pulmonary vasoconstriction, p > 0.05). Extracorporeal flow did not change coupling (0.0 [- 0.0 to 0.1] per change of 1 L/min, p > 0.05). End-diastolic volume increased with decreasing extracorporeal flow (7.2 [6.6 to 7.8] ml change per 1 L/min, p < 0.001). CONCLUSIONS: The right ventricle dilates with increased preload and increases its contractility in response to afterload changes to maintain ventricular-arterial coupling during VA extracorporeal membrane oxygenation.

Association between ABO blood type and coronavirus disease 2019 severe outcomes across dominant variant strains.

Objectives: Existing evidence suggests a link between ABO blood type and severe outcomes in coronavirus disease 2019 (COVID-19). We aimed to assess the relationship between blood type and severe outcomes across variant strains throughout the pandemic. Methods: This was a multicenter retrospective observational cohort analysis from a large health system in southeastern Michigan using electronic medical records to evaluate emergency encounters, hospitalization, and severe outcomes in COVID-19 based on ABO blood type. Consecutive adult patients presenting to the emergency department with a primary diagnosis of COVID-19 (U07.1) from March 1, 2020 through December 31, 2022 were assessed. Patients who presented during three distinct time intervals that coincided with Alpha, Delta, and Omicron variant predominance were included in the analysis. Exclusions included no record of ABO blood type, positive PCR COVID-19 test within the preceding 28 days, and if transferred from out of the health system. Severe outcomes were inclusive of intensive care unit admission, mechanical ventilation, or death, which, as a composite, represented our primary outcome. Secondary outcomes were hospital admission and length of stay. A logistic regression model was employed to test the association between ABO blood type and severe outcome, adjusting for age, sex, race, vaccination status, Elixhauser comorbidity indices, and the dominant variant time period in which the encounter occurred. Results: Of the 33,796 COVID-19 encounters, 9416 met inclusion criteria; 4071 (43.2%) were type O, 3417 (36.3%) were type A, 459 (4.9%) were type AB, and 1469 (15.6%) were type B blood. Note that 66.4% of the cohort was female (p = 0.18). The proportion of composite severe disease among the four blood types was similar and ranged between 8.6% and 8.9% (p = 0.98). Note that 53.0% of type A blood patients required hospital admission, compared to 51.9%, 50.4%, and 48.1% of type AB, B, and O blood, respectively (p < 0.001). Compared to patients with O blood type (43.2%), non-O blood type (58.8%; composite of A, AB, and B) exhibited no statistically significant difference in the proportion of composite severe disease (8.8% vs. 8.7%; p = 0.81) Multivariable regression analyses exhibited no significant difference regarding the presence of severe outcomes among the four blood types or O versus non-O blood types during T1, T2, and T3. Conclusions: ABO blood type was not associated with COVID-19 severe outcomes across the Delta, Alpha, and Omicron dominant COVID waves across a large health system in southeastern Michigan. Further research is needed to better understand if ABO blood type is a risk factor for severe disease among evolving COVID-19 variants and other viral upper respiratory infections.

Systematic approaches to assessing high-temperature limits to fertility in animals.

Critical thermal limits (CTLs) gauge the physiological impact of temperature on survival or critical biological function, aiding predictions of species range shifts and climatic resilience. Two recent Drosophila species studies, using similar approaches to determine temperatures that induce sterility (thermal fertility limits [TFLs]), reveal that TFLs are often lower than CTLs and that TFLs better predict both current species distributions and extinction probability. Moreover, many studies show fertility is more sensitive at less extreme temperatures than survival (thermal sensitivity of fertility [TSF]). These results present a more pessimistic outlook on the consequences of climate change. However, unlike CTLs, TFL data are limited to Drosophila, and variability in TSF methods poses challenges in predicting species responses to increasing temperature. To address these data and methodological gaps, we propose 3 standardized approaches for assessing thermal impacts on fertility. We focus on adult obligate sexual terrestrial invertebrates but also provide modifications for other animal groups and life-history stages. We first outline a "gold-standard" protocol for determining TFLs, focussing on the effects of short-term heat shocks and simulating more frequent extreme heat events predicted by climate models. As this approach may be difficult to apply to some organisms, we then provide a standardized TSF protocol. Finally, we provide a framework to quantify fertility loss in response to extreme heat events in nature, given the limitations in laboratory approaches. Applying these standardized approaches across many taxa, similar to CTLs, will allow robust tests of the impact of fertility loss on species responses to increasing temperatures.

BET-inhibitor DYB-41 reduces pulmonary inflammation and local and systemic cytokine levels in LPS-induced acute respiratory distress syndrome: an experimental rodent study.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a form of respiratory failure stemming from various underlying conditions that ultimately lead to inflammation and lung fibrosis. Bromodomain and Extra-Terminal motif (BET) inhibitors are a class of medications that selectively bind to the bromodomains of BET motif proteins, effectively reducing inflammation. However, the use of BET inhibitors in ARDS treatment has not been previously investigated. In our study, we induced ARDS in rats using endotoxin and administered a BET inhibitor. We evaluated the outcomes by examining inflammation markers and lung histopathology. RESULTS: Nine animals received treatment, while 12 served as controls. In the lung tissue of treated animals, we observed a significant reduction in TNFα levels (549 [149-977] pg/mg vs. 3010 [396-5529] pg/mg; p = 0.009) and IL-1ß levels (447 [369-580] pg/mg vs. 662 [523-924] pg/mg; p = 0.012), although IL-6 and IL-10 levels showed no significant differences. In the blood, treated animals exhibited a reduced TNFα level (25 [25-424] pg/ml vs. 900 [285-1744] pg/ml, p = 0.016), but IL-1ß levels were significantly higher (1254 [435-2474] pg/ml vs. 384 [213-907] pg/ml, p = 0.049). No differences were observed in IL-6 and IL-10 levels. There were no significant variations in lung tissue levels of TGF-ß, SP-D, or RAGE. Histopathological analysis revealed substantial damage, with notably less perivascular edema (3 vs 2; p = 0.0046) and visually more inflammatory cells. However, two semi-quantitative histopathologic scoring systems did not indicate significant differences. CONCLUSIONS: These preliminary findings suggest a potential beneficial effect of BET inhibitors in the treatment of acute lung injury and ARDS. Further validation and replication of these results with a larger cohort of animals, in diverse models, and using different BET inhibitors are needed to explore their clinical implications.

Causes of death in patients operated for colorectal cancer.

BACKGROUND: Colorectal cancer remains the third leading cause of cancer-related mortality in the United States. This study evaluates the causes of death in patients operated on for colorectal cancer and their determinants. METHODS: An Instructional Review Board-approved database containing patients who underwent surgical resection for colorectal cancer from 2004 to 2018 (last followed up in December 2020) in a tertiary care institution. Data on the underlying cause of death was extracted from the Registry of Vital Records and Statistics in Massachusetts. RESULTS: A total of 576 deaths were recorded in the database, of which 290 (50.35%) patients died of colorectal cancer. Deaths from colorectal cancer gradually decreased over time, whereas deaths from other cancers increased, and deaths from cardiovascular diseases remained stable. Patients who died from colorectal cancer were younger, died earlier in the disease course, had fewer comorbidities, higher rates of stage IV disease, rectal cancer, neoadjuvant therapy, extramural vascular invasion, perineural invasion, R0 resection, and preserved mismatch repair protein status. On multivariate analysis, age (adjusted odds ratio for 10-year increase = 0.79, 95% confidence interval 0.65-0.95), American Society of Anesthesiologists score (adjusted odds ratio = 0.64, confidence interval 0.42-0.98), stage IV disease (adjusted odds ratio = 3.02, confidence interval 1.59-5.9), neoadjuvant therapy (adjusted odds ratio = 7.91, confidence interval 2.64-28.13), extramural vascular invasion (adjusted odds ratio = 2.3, confidence interval 1.36-3.91) & time from diagnosis to death (adjusted odds ratio = 0.76, confidence interval 0.68-0.83) predicted death due to colorectal cancer versus other causes, whereas tumor location, perineural invasion, R0 resection, and mismatch repair protein status did not. CONCLUSION: There is a declining trend of deaths from colorectal cancer, presumably reflecting advances in colorectal cancer management strategies and better screening over time. However, younger patients disproportionately contribute to death due to colorectal cancer and need aggressive screening and management strategies.

The Impact of the Gut Microbiome, Environment, and Diet in Early-Onset Colorectal Cancer Development.

Traditionally considered a disease common in the older population, colorectal cancer is increasing in incidence among younger demographics. Evidence suggests that populational- and generational-level shifts in the composition of the human gut microbiome may be tied to the recent trends in gastrointestinal carcinogenesis. This review provides an overview of current research and putative mechanisms behind the rising incidence of colorectal cancer in the younger population, with insight into future interventions that may prevent or reverse the rate of early-onset colorectal carcinoma.

When and how can we predict adaptive responses to climate change?

Predicting if, when, and how populations can adapt to climate change constitutes one of the greatest challenges in science today. Here, we build from contributions to the special issue on evolutionary adaptation to climate change, a survey of its authors, and recent literature to explore the limits and opportunities for predicting adaptive responses to climate change. We outline what might be predictable now, in the future, and perhaps never even with our best efforts. More accurate predictions are expected for traits characterized by a well-understood mapping between genotypes and phenotypes and traits experiencing strong, direct selection due to climate change. A meta-analysis revealed an overall moderate trait heritability and evolvability in studies performed under future climate conditions but indicated no significant change between current and future climate conditions, suggesting neither more nor less genetic variation for adapting to future climates. Predicting population persistence and evolutionary rescue remains uncertain, especially for the many species without sufficient ecological data. Still, when polled, authors contributing to this special issue were relatively optimistic about our ability to predict future evolutionary responses to climate change. Predictions will improve as we expand efforts to understand diverse organisms, their ecology, and their adaptive potential. Advancements in functional genomic resources, especially their extension to non-model species and the union of evolutionary experiments and "omics," should also enhance predictions. Although predicting evolutionary responses to climate change remains challenging, even small advances will reduce the substantial uncertainties surrounding future evolutionary responses to climate change.

Heat stress reveals a fertility debt owing to postcopulatory sexual selection.

Climates are changing rapidly, demanding equally rapid adaptation of natural populations. Whether sexual selection can aid such adaptation is under debate; while sexual selection should promote adaptation when individuals with high mating success are also best adapted to their local surroundings, the expression of sexually selected traits can incur costs. Here we asked what the demographic consequences of such costs may be once climates change to become harsher and the strength of natural selection increases. We first adopted a classic life history theory framework, incorporating a trade-off between reproduction and maintenance, and applied it to the male germline to generate formalized predictions for how an evolutionary history of strong postcopulatory sexual selection (sperm competition) may affect male fertility under acute adult heat stress. We then tested these predictions by assessing the thermal sensitivity of fertility (TSF) in replicated lineages of seed beetles maintained for 68 generations under three alternative mating regimes manipulating the opportunity for sexual and natural selection. In line with the theoretical predictions, we find that males evolving under strong sexual selection suffer from increased TSF. Interestingly, females from the regime under strong sexual selection, who experienced relaxed selection on their own reproductive effort, had high fertility in benign settings but suffered increased TSF, like their brothers. This implies that female fertility and TSF evolved through genetic correlation with reproductive traits sexually selected in males. Paternal but not maternal heat stress reduced offspring fertility with no evidence for adaptive transgenerational plasticity among heat-exposed offspring, indicating that the observed effects may compound over generations. Our results suggest that trade-offs between fertility and traits increasing success in postcopulatory sexual selection can be revealed in harsh environments. This can put polyandrous species under immediate risk during extreme heat waves expected under future climate change.

Short-Stay Units vs Routine Admission From the Emergency Department in Patients With Acute Heart Failure: The SSU-AHF Randomized Clinical Trial.

Importance: More than 80% of patients who present to the emergency department (ED) with acute heart failure (AHF) are hospitalized. With more than 1 million annual hospitalizations for AHF in the US, safe and effective alternatives are needed. Care for AHF in short-stay units (SSUs) may be safe and more efficient than hospitalization, especially for lower-risk patients, but randomized clinical trial data are lacking. Objective: To compare the effectiveness of SSU care vs hospitalization in lower-risk patients with AHF. Design, Setting, and Participants: This multicenter randomized clinical trial randomly assigned low-risk patients with AHF 1:1 to SSU or hospital admission from the ED. Patients received follow-up at 30 and 90 days post discharge. The study began December 6, 2017, and was completed on July 22, 2021. The data were analyzed between March 27, 2020, and November 11, 2023. Intervention: Randomized post-ED disposition to less than 24 hours of SSU care vs hospitalization. Main Outcomes and Measures: The study was designed to detect at least 1-day superiority for a primary outcome of days alive and out of hospital (DAOOH) at 30-day follow-up for 534 participants, with an allowance of 10% participant attrition. Due to the COVID-19 pandemic, enrollment was truncated at 194 participants. Before unmasking, the primary outcome was changed from DAOOH to an outcome with adequate statistical power: quality of life as measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). The KCCQ-12 scores range from 0 to 100, with higher scores indicating better quality of life. Results: Of the 193 patients enrolled (1 was found ineligible after randomization), the mean (SD) age was 64.8 (14.8) years, 79 (40.9%) were women, and 114 (59.1%) were men. Baseline characteristics were balanced between arms. The mean (SD) KCCQ-12 summary score between the SSU and hospitalization arms at 30 days was 51.3 (25.7) vs 45.8 (23.8) points, respectively (P = .19). Participants in the SSU arm had 1.6 more DAOOH at 30-day follow-up than those in the hospitalization arm (median [IQR], 26.9 [24.4-28.8] vs 25.4 [22.0-27.7] days; P = .02). Adverse events were uncommon and similar in both arms. Conclusions and Relevance: The findings show that the SSU strategy was no different than hospitalization with regard to KCCQ-12 score, superior for more DAOOH, and safe for lower-risk patients with AHF. These findings of lower health care utilization with the SSU strategy need to be definitively tested in an adequately powered study. Trial Registration: ClinicalTrials.gov Identifier: NCT03302910.

Early intranasal medication administration in out-of-hospital cardiac arrest: Two randomized simulation trials.

Objective: Intranasal medications have been proposed as adjuncts to out-of-hospital cardiac arrest (OHCA) care. We sought to quantify the effects of intranasal medication administration (INMA) in OHCA workflows. Methods: We conducted separate randomized OHCA simulation trials with lay rescuers (LRs) and first responders (FRs). Participants were randomized to groups performing hands-only cardiopulmonary resuscitation (CPR)/automated external defibrillator with or without INMA during the second analysis phase. Time to compression following the second shock (CPR2) was the primary outcome and compression quality (chest compression rate (CCR) and fraction (CCF)) was the secondary outcome. We fit linear regression models adjusted for CPR training in the LR group and service years in the FR group. Results: Among LRs, INMA was associated with a significant increase in CPR2 (mean diff. 44.1 s, 95% CI: 14.9, 73.3), which persisted after adjustment (p = 0.005). We observed a significant decrease in CCR (INMA 95.1 compressions per min (cpm) vs control 104.2 cpm, mean diff. -9.1 cpm, 95% CI -16.6, -1.6) and CCF (INMA 62.4% vs control 69.8%, mean diff. -7.5%, 95% CI -12.0, -2.9). Among FRs, we found no significant CPR2 delays (mean diff. -2.1 s, 95% CI -15.9, 11.7), which persisted after adjustment (p = 0.704), or difference in quality (CCR INMA 115.5 cpm vs control 120.8 cpm, mean diff. -5.3 cpm, 95% CI -12.6, 2.0; CCF INMA 79.6% vs control 81.2% mean diff. -1.6%, 95% CI -7.4, 4.3%). Conclusions: INMA in LR resuscitation was associated with diminished resuscitation performance. INMA by FR did not impede key times or quality.

Environmental complexity mitigates the demographic impact of sexual selection.

Sexual selection and the evolution of costly mating strategies can negatively impact population viability and adaptive potential. While laboratory studies have documented outcomes stemming from these processes, recent observations suggest that the demographic impact of sexual selection is contingent on the environment and therefore may have been overestimated in simple laboratory settings. Here we find support for this claim. We exposed copies of beetle populations, previously evolved with or without sexual selection, to a 10-generation heatwave while maintaining half of them in a simple environment and the other half in a complex environment. Populations with an evolutionary history of sexual selection maintained larger sizes and more stable growth rates in complex (relative to simple) environments, an effect not seen in populations evolved without sexual selection. These results have implications for evolutionary forecasting and suggest that the negative demographic impact of sexually selected mating strategies might be low in natural populations.

Metformin Does not Affect Outcomes in Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Therapy and Resection.

INTRODUCTION: There is emerging evidence that metformin may have a protective effect in patients with cancer. However, its current evidence in locally advanced rectal cancer (LARC) is inconclusive. We aim to assess the effect of metformin on long-term outcomes in patients with LARC who received neoadjuvant therapy and surgical resection. METHODS: A retrospective review of 324 patients with nonmetastatic LARC who received neoadjuvant therapy and major surgical resection from 2004 to 2018. There were 27 patients who received metformin before surgery and 297 patients who did not receive metformin. RESULTS: Metformin users were associated with a significantly higher age, BMI, ASA score, and 30-day readmissions (P < .05). There was no difference in overall survival (OS, P = .18) or disease-free survival (DFS, P = .33) between the two groups. On Cox regression, metformin intake did not predict OS (HR 0.85, 95% CI 0.4-1.77) when controlled for age (HR 1.04, 1.02-1.06), sex (HR 1.13, 0.69-1.85), BMI (HR 0.97, 0.92-1.02), ASA score (HR: 1.7, 1.06-2.73), TNT (HR 0.31, 0.1-0.92), pathological Stage III disease (HR 2.55, 1.51-4.32), extramural vascular invasion (EMVI) (HR 3.06, 1.7-5.5), and adjuvant therapy (HR 0.1, 0.04-0.27 for <25 months OS and HR 0.3, 0.15-0.59 for ≥25 months). Disease-free survival showed a similar trend with no significant effect of metformin (HR 0.77, 0.39-1.52) when controlled for age, sex, BMI, ASA, TNT, Stage III disease, EMVI, and adjuvant therapy. CONCLUSION: Metformin does not affect long-term survival in LARC treated with neoadjuvant therapy followed by surgical resection. Studies with larger sample sizes are needed to validate the findings further.

Association Between Coronavirus Disease 2019 Vaccination and Mortality After Major Operations.

OBJECTIVE: The objective of this study was to compare postoperative 90-day mortality between (1) fully vaccinated patients with COVID-19-positive and negative diagnosis, and (2) vaccinated and unvaccinated patients with COVID-19 positive diagnosis. BACKGROUND: Societal guidelines recommend postponing elective operations for at least 7 weeks in unvaccinated patients with preoperative coronavirus disease 2019 (COVID-19) infection. The role of vaccination in this infection-operation time risk is unclear. METHODS: We conducted a national US multicenter retrospective, matched cohort study spanning July 2021 to October 2022. Participants were included if they underwent a high-risk general, vascular, orthopedic, neurosurgery, or genitourinary surgery. All-cause mortality occurring within 90 days of the index operation was the primary outcome. Inverse probability treatment weighted propensity scores were used to adjust logistic regression models examining the independent and interactive associations between mortality, exposure status, and infection proximity. RESULTS: Of 3401 fully vaccinated patients in the 8-week preoperative period, 437 (12.9%) were COVID-19-positive. Unadjusted mortality rates were not significantly different between vaccinated patients with COVID-19 (22, 5.0%) and vaccinated patients without COVID-19 (99, 3.3%; P = 0.07). After inverse probability treatment weighted adjustment, mortality risk was not significantly different between vaccinated COVID-19-positive patients compared to vaccinated patients without COVID-19 (adjusted odds ratio = 1.38, 95% CI: 0.70, 2.72). The proximity of COVID-19 diagnosis to the index operation did not confer added mortality risk in either comparison cohort. CONCLUSIONS: Contrary to risks observed among unvaccinated patients, postoperative mortality does not differ between patients with and without COVID-19 when vaccinated against the severe acute respiratory syndrome coronavirus 2 virus and receiving a high-risk operation within 8 weeks of the diagnosis, regardless of operation timing relative to diagnosis.

Trends and Determinants of Location of Death Due to Colorectal Cancer in the United States : A Nationwide Study.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States (US); however, there are limited data on location of death in patients who die from CRC. We examined the trends in location of death and determinants in patients dying from CRC in the US. METHODS: We utilized the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database to extract nationwide data on underlying cause of death as CRC. A multinomial logistic regression was performed to assess associations between clinico-sociodemographic characteristics and location of death. RESULTS: There were 850,750 deaths due to CRC from 2003 to 2019. There was a gradual decrease in deaths in hospital, nursing home, or outpatient facility/emergency department over time and an increase in deaths at home and in hospice. Relative to White decedents, Black, Asian, and American Indian/Alaska Native decedents were less likely to die at home and in hospice compared with hospitals. Individuals with lower educational status also had a lower risk of dying at home or in hospice compared with in hospitals. CONCLUSIONS: The gradual shift in location of death of patients who die of CRC from institutionalized settings to home and hospice is a promising trend and reflects the prioritization of patient goals for end-of-life care by healthcare providers. However, there are existing sociodemographic disparities in access to deaths at home and in hospice, which emphasizes the need for policy interventions to reduce health inequity in end-of-life care for CRC.

Incidence of Secondary Cancers After Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

INTRODUCTION: Whether neoadjuvant chemoradiation for locally advanced rectal cancer (LARC) induces secondary cancers is controversial. This retrospective cohort study describes the incidence of secondary cancers in LARC patients. METHODS: We compared 364 LARC patients who received conventional (50.4 Gy) or short course neoadjuvant radiation (25 Gy x 5 fractions) followed by resection to 142 patients with surgically resected rectal cancer who did not receive radiation at a single institution from 2004 to 2018. Secondary cancer was defined as any nonmetastatic noncolorectal malignancy diagnosed via biopsy or definitive imaging criteria at least 6 mo after completion of neoadjuvant therapy or after resection in the comparison group. RESULTS: Among the neoadjuvant radiation group (364 patients, 40% female, age 61 ± 13 y), 32 patients developed 34 (9.3%) secondary cancers. Three cases involved a pelvic organ. Among the comparison group (142 patients, 39% female, age 64 ± 15 y), 15 patients (10.6%) developed a secondary cancer. Five cases involved pelvic organs. Secondary cancer incidence did not differ between groups. Latency period to secondary cancer diagnosis was 6.7 ± 4.3 y. Patients who received radiation underwent longer median follow-up (6.8 versus 4.5 y, P < 0.01) and were significantly less likely to develop a pelvic organ cancer (odds ratio 0.18; 95% confidence interval, 0.04-0.83; P = 0.02). No genetic mutations or cancer syndromes were identified among patients with secondary cancers. CONCLUSIONS: Neoadjuvant chemoradiation is not associated with increased secondary cancer risk in LARC patients and may have a local protective effect on pelvic organs, especially prostate. Ongoing follow-up is critical to continue risk assessment.

Modified Thermodilution for Simultaneous Cardiac Output and Recirculation Assessment in Veno-venous Extracorporeal Membrane Oxygenation: A Prospective Diagnostic Accuracy Study.

BACKGROUND: Thermodilution is unreliable in veno-venous extracorporeal membrane oxygenation (VV-ECMO). Systemic oxygenation depends on recirculation fractions and ratios of extracorporeal membrane oxygenation (ECMO) flow to cardiac output. In a prospective in vitro simulation, this study assessed the diagnostic accuracy of a modified thermodilution technique for recirculation and cardiac output. The hypothesis was that this method provided clinically acceptable precision and accuracy for cardiac output and recirculation. METHODS: Two ECMO circuits ran in parallel: one representing a VV-ECMO and the second representing native heart, lung, and circulation. Both circuits shared the right atrium. Extra limbs for recirculation and pulmonary shunt were added. This study simulated ECMO flows from 1 to 2.5 l/min and cardiac outputs from 2.5 to 3.5 l/min with recirculation fractions (0 to 80%) and pulmonary shunts. Thermistors in both ECMO limbs and the pulmonary artery measured the temperature changes induced by cold bolus injections into the arterial ECMO limb. Recirculation fractions were calculated from the ratio of the areas under the temperature curve (AUCs) in the ECMO limbs and from partitioning of the bolus volume (flow based). With known partitioning of bolus volumes between ECMO and pulmonary artery, cardiac output was calculated. High-precision ultrasonic flow probes served as reference for Bland-Altman plots and linear mixed-effect models. RESULTS: Accuracy and precision for both the recirculation fraction based on AUC (bias, -5.4%; limits of agreement, -18.6 to 7.9%) and flow based (bias, -5.9%; limits of agreement, -18.8 to 7.0%) are clinically acceptable. Calculated cardiac output for all recirculation fractions was accurate but imprecise (RecirculationAUC: bias 0.56 l/min; limits of agreement, -2.27 to 3.4 l/min; and RecirculationFLOW: bias 0.48 l/min; limits of agreement, -2.22 to 3.19 l/min). Recirculation fraction increased bias and decreased precision. CONCLUSIONS: Adapted thermodilution for VV-ECMO allows simultaneous measurement of recirculation fraction and cardiac output and may help optimize patient management with severe respiratory failure.