Distinctive profile of monomeric and polymeric anti-SSA/Ro52 immunoglobulin A1 isoforms in saliva of patients with primary Sjögren's syndrome and Sicca.

OBJECTIVE: Primary Sjögren's syndrome (pSS) is the second most common chronic autoimmune connective tissue disease. Autoantibodies, immunoglobulin (IgG) anti-SSA/Ro, in serum is a key diagnostic feature of pSS. Since pSS is a disease of the salivary gland, we investigated anti-SSA/Ro52 in saliva. METHODS: Using a novel electrochemical detection platform, Electric Field-Induced Release and Measurement, we measured IgG/M/A, IgG, IgA, IgA isotypes (IgA1 and IgA2) and IgA1 subclasses (polymeric and monomeric IgA1) to anti-SSA/Ro52 in saliva supernatant of 34 pSS, 35 dry eyes and dry mouth (patients with Sicca) and 41 health controls. RESULTS: Saliva IgG/M/A, IgG, IgA, IgA isotypes and IgA1 subclasses to anti-SSA/Ro52 differed significantly between pSS, non-pSS Sicca and healthy subjects. Elevated monomeric IgA1 was observed in patients with non-pSS Sicca while elevated polymeric IgA1 (pIgA1) was observed in patients with pSS. Salivary polymeric but not monomeric IgA1 (mIgA1) isoform correlated with focus score (r2=0.467, p=0.001) CONCLUSIONS: Salivary anti-Ro52 polymeric IgA1 isoform is associated with glandular inflammation in pSS, while salivary monomeric IgA1 is associated with Sicca. Whether IgA1 isotope switching plays a role in the progression of the Sicca to pSS warrants further investigation.

A Prospective Observational Cohort Study of Language Preference and Preoperative Cognitive Screening in Older Adults: Do Language Disparities Exist in Cognitive Screening and Does the Association Between Test Results and Postoperative Delirium Differ Based on Language Preference?

BACKGROUND: A greater percentage of surgical procedures are being performed each year on patients 65 years of age or older. Concurrently, a growing proportion of patients in English-speaking countries such as the United States, United Kingdom, Australia, and Canada have a language other than English (LOE) preference. We aimed to measure whether patients with LOE underwent cognitive screening at the same rates as their English-speaking counterparts when routine screening was instituted. We also aimed to measure the association between preoperative Mini-Cog and postoperative delirium (POD) in both English-speaking and LOE patients. METHODS: We conducted a single-center, observational cohort study in patients 65 years old or older, scheduled for surgery and evaluated in the preoperative clinic. Cognitive screening of older adults was recommended as an institutional program for all patients 65 and older presenting to the preoperative clinic. We measured program adherence for cognitive screening. We also assessed the association of preoperative impairment on Mini-Cog and POD in both English-speaking and LOE patients, and whether the association differed for the 2 groups. A Mini-Cog score ≤2 was considered impaired. Postoperatively, patients were assessed for POD using the Confusion Assessment Method (CAM) and by systematic chart review. RESULTS: Over a 3-year period (February 2019-January 2022), 2446 patients 65 years old or older were assessed in the preoperative clinic prior. Of those 1956 patients underwent cognitive screening. Eighty-nine percent of English-speaking patients underwent preoperative cognitive screening, compared to 58% of LOE patients. The odds of having a Mini-Cog assessment were 5.6 times higher (95% confidence interval [CI], 4.6-7.0) P < .001 for English-speaking patients compared to LOE patients. In English-speaking patients with a positive Mini-Cog screen, the odds of having postop delirium were 3.5 times higher (95% CI, 2.6-4.8) P < .001 when compared to negative Mini-Cog. In LOE patients, the odds of having postop delirium were 3.9 times higher (95% CI, 2.1-7.3) P < .001 for those with a positive Mini-Cog compared to a negative Mini-Cog. The difference between these 2 odds ratios was not significant (P = .753). CONCLUSIONS: We observed a disparity in the rates LOE patients were cognitively screened before surgery, despite the Mini-Cog being associated with POD in both English-speaking and LOE patients. Efforts should be made to identify barriers to cognitive screening in limited English-proficient older adults.

Impact of Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography on Prostate Cancer Salvage Radiotherapy Management: Results from a Prospective Multicenter Randomized Phase 3 Trial (PSMA-SRT NCT03582774).

BACKGROUND: Both imaging and several prognostic factors inform the planning of salvage radiotherapy (SRT). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can localize disease unseen by other imaging modalities. OBJECTIVE: To evaluate the impact of PSMA-PET on biochemical recurrence-free survival rate after SRT. DESIGN, SETTING, AND PARTICIPANTS: This prospective randomized, controlled, phase 3 clinical trial randomized 193 patients with biochemical recurrence of prostate cancer after radical prostatectomy to proceed with SRT (control arm, n = 90) or undergo a PSMA-PET/computed tomography (CT) scan prior to SRT planning (investigational arm, n = 103) from June 2018 to August 2020. Any other approved imaging modalities were allowed in both arms (including fluciclovine-PET). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: This is a secondary endpoint analysis: impact of PSMA-PET on SRT planning. Case-report forms were sent to referring radiation oncologists to collect the management plans before randomization and after completion of SRT. The relative frequency (%) of management changes within each arm were compared using chi-square and Fisher's exact tests. RESULTS AND LIMITATIONS: The delivered SRT plan was available in 178/193 patients (92.2%; 76/90 control [84.4%] and 102/103 PSMA-PET [99%]). Median prostate-specific antigen levels at enrollment was 0.30 ng/ml (interquartile range [IQR] 0.19-0.91) in the control arm and 0.23 ng/ml (IQR 0.15-0.54) in the PSMA-PET arm. Fluciclovine-PET was used in 33/76 (43%) in the control arm. PSMA-PET localized recurrence(s) in 38/102 (37%): nine of 102 (9%) outside of the pelvis (M1), 16/102 (16%) in the pelvic LNs (N1, with or without local recurrence), and 13/102 (13%) in the prostate fossa only. There was a 23% difference (95% confidence interval [CI] 9-35%, p = 0.002) of frequency of major changes between the control arm (22% [17/76]) and the PSMA-PET intervention arm (45% [46/102]). Of the major changes in the intervention group, 33/46 (72%) were deemed related to PSMA-PET. There was a 17.6% difference (95% CI 5.4-28.5%, p = 0.005) of treatment escalation frequency between the control arm (nine of 76 [12%]) and the intervention arm (30/102 [29%]). Treatment de-escalation occurred in the control and intervention arms in eight of 76 (10.5%) and 12/102 (11.8%) patients, and mixed changes in zero of 76 (0%) and four of 102 (3.9%) patients, respectively. CONCLUSIONS: In this prospective randomized phase 3 study, PSMA-PET findings provided information that initiated major management changes to SRT planning in 33/102 (33%) patients. The final readout of the primary endpoint planned in 2025 may provide evidence on whether these changes result in improved outcomes. PATIENT SUMMARY: Prostate-specific membrane antigen positron emission tomography leads to management changes in one-third of patients receiving salvage radiotherapy for post-radical prostatectomy biochemical recurrence of prostate cancer.

Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma.

Increased utilization of glucose is a hallmark of cancer. Sodium-glucose transporter 2 (SGLT2) is a critical player in glucose uptake in early-stage and well-differentiated lung adenocarcinoma (LUAD). SGLT2 inhibitors, which are FDA approved for diabetes, heart failure, and kidney disease, have been shown to significantly delay LUAD development and prolong survival in murine models and in retrospective studies in diabetic patients, suggesting that they may be repurposed for lung cancer. Despite the antitumor effects of SGLT2 inhibition, tumors eventually escape treatment. Here, we studied the mechanisms of resistance to glucose metabolism-targeting treatments. Glucose restriction in LUAD and other tumors induced cancer cell dedifferentiation, leading to a more aggressive phenotype. Glucose deprivation caused a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. The dedifferentiated phenotype depended on unbalanced EZH2 activity that suppressed prolyl-hydroxylase PHD3 and increased expression of hypoxia-inducible factor 1α (HIF1α), triggering epithelial-to-mesenchymal transition. Finally, a HIF1α-dependent transcriptional signature of genes upregulated by low glucose correlated with prognosis in human LUAD. Overall, this study furthers current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying targets to prevent the development of resistance to therapies targeting glucose metabolism. SIGNIFICANCE: Epigenetic adaptation allows cancer cells to overcome the tumor-suppressive effects of glucose restriction by inducing dedifferentiation and an aggressive phenotype, which could help design better metabolic treatments.

Utility of preoperative troponin I to predict mortality in adult liver transplant recipients: Revisiting pretransplant cardiac risk in the current MELD-allocation era.

BACKGROUND: Preoperative risk assessment in liver transplant (LT) candidates, particularly related to cardiac risk, is an area of intense interest for transplant clinicians. Various cardiac testing methods are employed by transplant centers to characterize cardiac risk. Serum troponin is an established method for the detection of myocardial injury in a wide variety of clinical settings. Preoperative troponin screening has been reported to predict postoperative cardiac events and mortality in various surgical patient populations, however, the utility of preoperative troponin to predict posttransplant outcomes in current LT candidate populations requires further investigation. METHODS: We performed a prospective blinded study in a cohort of 275 consecutive LT recipients at a single transplant center to determine if preoperative serum troponin I (TnI) was predictive for postoperative 1-year mortality. RESULTS: Abnormal preoperative TnI levels (>.1 ng/mL) were found in 38 patients (14%). One-year mortality occurred in 19 patients (7%). There was no significant difference in mortality between patients with normal and abnormal troponin levels. Additionally, we found that there was no significant difference in early postoperative major adverse cardiac events between patient groups. CONCLUSIONS: Contrary to previous reports, elevated preoperative TnI was not significantly predictive of posttransplant mortality in LT recipients at our institution.

Evaluating the Impact of Race and Ethnicity on Health-Related Quality of Life Disparities in Patients with Esophageal Cancer: A SEER-MHOS National Database Study.

BACKGROUND: It is unclear whether health-related quality of life (HRQOL) disparities exist between racial/ethnic groups in older patients with esophageal cancer, pre- and post-diagnosis. METHODS: Using the SEER-MHOS (Surveillance, Epidemiology, and End Results and Medicare Health Outcomes Survey) national database, we included patients ages 65-years-old or greater with esophageal cancer diagnosed from 1996 to 2017. HRQOL data within 36 months before and after diagnosis were measured by the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores from the SF-36 and VR-12 instruments. Total combined score (TCS) was reflected by both PCS and MCS. RESULTS: We identified 1,312 patients, with evaluable data on 873 patients pre-diagnosis and 439 post-diagnosis. On pre-diagnosis cohort MVA, the MCS was better for White over Hispanic patients (54.1 vs. 48.6, P = 0.012). On post-diagnosis cohort MVA, PCS was better for Hispanic compared with White (39.8 vs. 34.5, P = 0.036) patients, MCS was better for Asian compared with White (48.9 vs. 40.9, P = 0.034) patients, and TCS better for Asian compared with White (92.6 vs. 76.7, P = 0.003) patients. CONCLUSIONS: In older patients with esophageal cancer, White patients had better mental HRQOL as compared with Hispanic patients pre-diagnosis. However, post-diagnosis, White patients had worse mental and physical HRQOL compared with Asian and Hispanic patients, respectively, suggesting a greater negative impact on self-reported HRQOL in White patients with esophageal cancer. IMPACT: To our knowledge, this study is the first to explore HRQOL differences in patients with esophageal cancer of various racial and ethnic groups and warrants further validation in future studies.

External validation of a predictive model for reintubation after cardiac surgery: A retrospective, observational study.

STUDY OBJECTIVE: Explore validation of a model to predict patients' risk of failing extubation, to help providers make informed, data-driven decisions regarding the optimal timing of extubation. DESIGN: We performed temporal, geographic, and domain validations of a model for the risk of reintubation after cardiac surgery by assessing its performance on data sets from three academic medical centers, with temporal validation using data from the institution where the model was developed. SETTING: Three academic medical centers in the United States. PATIENTS: Adult patients arriving in the cardiac intensive care unit with an endotracheal tube in place after cardiac surgery. INTERVENTIONS: Receiver operating characteristic (ROC) curves and concordance statistics were used as measures of discriminative ability, and calibration curves and Brier scores were used to assess the model's predictive ability. MEASUREMENTS: Temporal validation was performed in 1642 patients with a reintubation rate of 4.8%, with the model demonstrating strong discrimination (optimism-corrected c-statistic 0.77) and low predictive error (Brier score 0.044) but poor model precision and recall (Optimal F1 score 0.29). Combined domain and geographic validation were performed in 2041 patients with a reintubation rate of 1.5%. The model displayed solid discriminative ability (optimism-corrected c-statistic = 0.73) and low predictive error (Brier score = 0.0149) but low precision and recall (Optimal F1 score = 0.13). Geographic validation was performed in 2489 patients with a reintubation rate of 1.6%, with the model displaying good discrimination (optimism-corrected c-statistic = 0.71) and predictive error (Brier score = 0.0152) but poor precision and recall (Optimal F1 score = 0.13). MAIN RESULTS: The reintubation model displayed strong discriminative ability and low predictive error within each validation cohort. CONCLUSIONS: Future work is needed to explore how to optimize models before local implementation.

Randomized Controlled Trial of Acupressure for Perception of Stress and Health-Related Quality of Life Among Health Care Providers During the COVID-19 Pandemic: The Self-Acupressure for Stress (SAS) Trial.

Background: The efficacy of providing self-acupressure educational materials in reducing stress and improving health-related quality of life (HRQOL) is uncertain. Evidence-based data to recommend for or against self-acupressure as an intervention for reducing stress and improving HRQOL is needed. Objective: The Self-Acupressure for Stress (SAS) trial evaluates whether providing self-acupressure educational materials would reduce stress and improve HRQOL among health care providers (HCPs). Design: Randomized behavioral clinical trial. Setting: The entire study took place remotely. Participants: One hundred fifty-nine adult HCPs with no prior experience or training in acupressure. Intervention: The intervention group received self-acupressure educational materials. Measurements: Primary outcomes were perception of stress measured by the Perceived Stress Scale (PSS), as well as scores on the physical and mental components of the 12-item Short Form Health Survey version 2 (SF-12v2). Results: From the baseline to midpoint evaluations, the intervention group significantly reduced their PSS score (P ≤ .001) and increased their SF-12v2 Mental score (P = .002) but not their SF-12v2 Physical score (P = .55). These findings persisted at the final follow-up (both PSS and SF-12v2 Mental changes from baseline P < .001). However the control group also significantly improved their SF-12v2 Mental from baseline to midpoint (P = .01) which was maintained at final follow-up (P = .02), whereas PSS and SF-12v2 Physical did not significantly change from baseline at either mid or final. Finally, the intervention group improved by significantly more than the control group from baseline to final follow-up for both PSS (P = .007) and SF-12v2 Mental (P = .02) HRQOL measures. Limitation: The trial was not blinded. Conclusion: Among HCPs during the coronavirus disease 2019 (COVID-19) pandemic, the provision of self-acupressure educational materials safely improved self-reported assessments of perception of stress and mental health. Self-acupressure represents a promising intervention for other populations. The study findings support the use of self-acupressure to reduce stress and improve HRQOL. Trial Registration: ClinicalTrials.gov: NCT04472559.

Effects of novel androgen receptor signaling inhibitors on PSMA PET signal intensity in patients with castrate-resistant prostate cancer: a prospective exploratory serial imaging study.

BACKGROUND: PSMA expression is influenced by hormonal status. We evaluated changes in PSA and whole-body 68Ga-PSMA-11 PET/CT (WB-PSMA PET) after initiation of androgen receptor signaling inhibitors (ARSi). METHODS: Prospectively enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) initiating ARSi underwent serial PSA measurements and WB-PSMA PET at baseline, 1-week, and 3-months post-ARSi. We correlated WB-PSMA PET metrics and PSA kinetics after ARSi to 1-year clinical outcome. RESULTS: Due to low enrollment rate, the study was closed before reaching the recruitment goal of 30 patients. Nine patients were enrolled. At 1-year, unfavorable outcome was documented in 6/9 (66%) patients. Nine/9 patients completed PSMA PET at 1-week, 5/9 at 3-months. Changes in PSA, PSMA-VOL, SUVmean and SUVmax were - 12%, + 5%, + 3%, and + 10% at 1-week, - 42%, - 16%, - 15% and - 17% at 3-months, respectively. CONCLUSIONS: Our prospective trial involving 9 mCRPC patients initiating ARSi did not show significant modulation of PSMA expression measured on WB-PSMA PET at 1-week. This study was registered on clinicaltrials.gov (NCT04279561).

Effect of omega-3 fatty acid diet on prostate cancer progression and cholesterol efflux in tumor-associated macrophages-dependence on GPR120.

BACKGROUND: Preclinical and clinical translational research supports the role of an ω-3 fatty acid diet for prostate cancer prevention and treatment. The anti-prostate cancer effects of an ω-3 diet require a functional host g-protein coupled receptor 120 (GPR120) but the underlying effects on the tumor microenvironment and host immune system are yet to be elucidated. METHODS: Friend leukemia virus B (FVB) mice received bone marrow from green fluorescent protein (GFP) labeled GPR120 wild-type (WT) or knockout (KO) mice followed by implanting Myc-driven mouse prostate cancer (MycCap) allografts and feeding an ω-3 or ω-6 diet. Tumor associated immune cells were characterized by flow cytometry, and CD206+ tumor infiltrating M2-like macrophages were isolated for gene expression studies. MycCap prostate cancer cell conditioned medium (CM) was used to stimulate murine macrophage cells (RAW264.7) and bone marrow-derived (BMD) macrophages to study the effects of docosahexanoic acid (DHA, fish-derived ω-3 fatty acid) on M2 macrophage function and cholesterol metabolism. RESULTS: The bone marrow transplantation study showed that an ω-3 as compared to an ω-6 diet inhibited MycCaP allograft tumor growth only in mice receiving GPR120 WT but not GPR120 KO bone marrow. In the ω-3 group, GPR120 WT BMD M2-like macrophages infiltrating the tumor were significantly reduced in number and gene expression of cholesterol transporters Abca1, Abca6, and Abcg1. RAW264.7 murine macrophages and BMDMs exposed to MycCaP cell CM had increased gene expression of cholesterol transporters, depleted cholesterol levels, and were converted to the M2 phenotype. These effects were inhibited by DHA through the GPR120 receptor. CONCLUSION: Host bone marrow cells with functional GPR120 are essential for the anticancer effects of dietary ω-3 fatty acids, and a key target of the ω-3 diet are the M2-like CD206+ macrophages. Our preclinical findings provide rationale for clinical trials evaluating ω-3 fatty acids as a potential therapy for prostate cancer through inhibition of GPR120 functional M2-like macrophages.

Prognostic Value of End-of-Treatment PSMA PET/CT in Patients Treated with 177Lu-PSMA Radioligand Therapy: A Retrospective, Single-Center Analysis.

Our objective was to evaluate the prognostic value of end-of-treatment prostate-specific membrane antigen (PSMA) PET/CT (PSMA-PET) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA radioligand therapy (PSMA-RLT). Methods: This was a single-center retrospective study. mCRPC patients who underwent PSMA-RLT with available baseline PSMA-PET (bPET) and end-of-treatment PSMA-PET (ePET) within 6 mo of the last PSMA-RLT cycle were eligible. Overall survival (OS) and prostate-specific antigen (PSA) progression status at the time of ePET (by Prostate Cancer Clinical Trials Working Group 3 criteria) were collected. PSMA-PET tumor segmentation was performed to obtain whole-body PSMA tumor volume (PSMA-VOL) and define progressive (≥20% increase) versus nonprogressive disease. Pairs of bPET and ePET were interpreted for appearance of new lesions. Response Evaluation Criteria in PSMA-PET/CT (RECIP) 1.0 were also applied to define progressive versus nonprogressive disease. The associations between changes in PSMA-VOL, new lesions, RECIP 1.0, and PSA progression status at the time of ePET with OS were evaluated by Kaplan-Meier analysis. Results: Twenty mCRPC patients were included. The median number of treatment cycles was 3.5 (interquartile range [IQR], 2-4). The median time between bPET and cycle 1 of PSMA-RLT was 1.0 mo (IQR, 0.7-1.8 mo). The median time between the last cycle of PSMA-RLT and ePET was 1.9 mo (IQR, 1.2-3.5 mo). Twelve of 20 patients (60%) had died at the last follow-up. The median follow-up time from ePET for survivors was 31.2 mo (IQR, 6.8-40.7 mo). The median OS from ePET was 11.4 mo (IQR, 6.8-30.7 mo). Patients with new lesions on ePET had shorter OS than those without new lesions (median OS, 10.7 mo [95% CI, 9.2-12.2] vs. not reached; P = 0.002). Patients with progressive PSMA-VOL had shorter OS than those with nonprogressive PSMA-VOL (median OS, 10.7 mo [95% CI: 9.7-11.7 mo] vs. not reached; P = 0.007). Patients with progressive RECIP had shorter OS than those with nonprogressive RECIP (median OS, 10.7 mo [95% CI, 9.7-11.7 mo] vs. not reached; P = 0.007). PSA progression at the time of ePET was associated with shorter OS (median, 10.9 mo [95% CI, 9.4-12.4 mo] vs. not reached; P = 0.028). Conclusion: In this retrospective study of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by the appearance of new lesions, changes in PSMA-VOL, and RECIP 1.0 was prognostic for OS. Validation in larger, prospective multicentric clinical trials is warranted.

Incidence of Intraoperative Vasoplegic Syndrome in Lung Transplantation.

OBJECTIVES: Severe hypotension and low systemic vascular resistance in the setting of adequate cardiac output, known as "vasoplegic syndrome" (VS), is a physiologic disturbance reported in 9% to 44% of cardiac surgery patients. Although this phenomenon is well-documented in cardiac surgery, there are few studies on its occurrence in lung transplantation. The goal of this study was to characterize the incidence of VS in lung transplantation, as well as identify associated risk factors and outcomes. DESIGN: Retrospective study of single and bilateral lung transplants from April 2013 to September 2021. SETTING: The study was conducted at an academic hospital. PARTICIPANTS: Patients ≥18 years of age who underwent lung transplantation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors defined VS as mean arterial pressure <65 mmHg, cardiac index ≥2.2 L/min/m2, and ≥30 minutes of vasopressor administration after organ reperfusion. The association between VS and risk factors or outcomes was assessed using t tests, Mann-Whitney U, and chi-square tests. The authors ran multivariate logistic regression models to determine factors independently associated with VS. The incidence of VS was 13.9% (CI 10.4%-18.4%). In the multivariate model, male sex (odds ratio 2.85, CI 1.07-7.58, p = 0.04) and cystic fibrosis (odds ratio 5.76, CI 1.43-23.09, p = 0.01) were associated with VS. CONCLUSIONS: The incidence of VS in lung transplantation is comparable to that of cardiac surgery. Interestingly, male sex and cystic fibrosis are strong risk factors. Identifying lung transplant recipients at increased risk of VS may be crucial to anticipating intraoperative complications.

Consent document translation expense hinders inclusive clinical trial enrolment.

Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA1-3. As these patients often have limited English proficiency4-7, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor). Here we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry-sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient's primary language in studies without industry sponsorship was approximately half of that seen in industry-sponsored studies. The results suggest that the cost of consent document translation in trials not sponsored by industry could be a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

A Pilot Single-Site Randomized Control Trial: Investigating the Use of Donor Milk in Late Preterm and Term Infants in the Neonatal Intensive Care Unit.

OBJECTIVE: We aimed to study donor milk (DM) supplementation when mother's own milk (MOM) was unavailable in term and late preterm infants (LPIs) admitted to the neonatal intensive care unit (NICU). We hypothesized that this study would be feasible, defined by the rate of consent, diet adherence, and study completion. We further hypothesized that compared with formula supplementation, DM supplementation, for no longer than 7 days from birth, would be associated with an increase in breastfeeding attempts and the percentage of MOM (MOM%) without adversely affecting growth. Breastfeeding attempts and MOM% were assessed over 48 hours at the end of the intervention, which was defined as NICU discharge or at the end of supplementation, whichever came sooner. STUDY DESIGN: This was a pilot study (n = 32). Infants with a gestational age > 34 weeks admitted to the NICU were included. Infants were randomized to one of two groups: human milk (MOM + DM) or formula (MOM + F). RESULTS: The consent rate was 52%. Adherence to the study diet was 97%, and completion was 100%. When the MOM + DM group was compared with the MOM + F group, there was no difference in breastfeeding attempts (median [interquartile range]: 3.5 [1.5-6] vs. 1.5 [0.5-4] times, p = 0.1) or MOM% (60 vs. 59%, p = 0.9). Weight and length at multiple time points were similar when the groups were compared. CONCLUSION: A study randomizing term and LPIs in the NICU to DM or formula when MOM was unavailable is feasible. It remains unclear if DM improves breastfeeding success in this population. KEY POINTS: · A study that randomizes term and late preterm infants in the NICU to DM or formula supplementation when mother's own milk is not available is feasible.. · It remains unclear if DM compared to formula supplementation improves direct breastfeeding.. · In general, growth was similar in infants who received DM or formula as a supplement..

Warning symptoms associated with imminent sudden cardiac arrest: a population-based case-control study with external validation.

BACKGROUND: Sudden cardiac arrest is a global public health problem with a mortality rate of more than 90%. Prearrest warning symptoms could be harnessed using digital technology to potentially improve survival outcomes. We aimed to estimate the strength of association between symptoms and imminent sudden cardiac arrest. METHODS: We conducted a case-control study of individuals with sudden cardiac arrest and participants without sudden cardiac arrest who had similar symptoms identified from two US community-based studies of patients with sudden cardiac arrest in California state, USA (discovery population; the Ventura Prediction of Sudden Death in Multi-Ethnic Communities [PRESTO] study), and Oregon state, USA (replication population; the Oregon Sudden Unexpected Death Study [SUDS]). Participant data were obtained from emergency medical services reports for people aged 18-85 years with witnessed sudden cardiac arrest (between Feb 1, 2015, and Jan 31, 2021) and an inclusion symptom. Data were also obtained from corresponding control populations without sudden cardiac arrest who were attended by emergency medical services for similar symptoms (between Jan 1 and Dec 31, 2019). We evaluated the association of symptoms with sudden cardiac arrest in the discovery population and validated our results in the replication population by use of logistic regression models. FINDINGS: We identified 1672 individuals with sudden cardiac arrest from the PRESTO study, of whom 411 patients (mean age 65·7 [SD 12·4] years; 125 women and 286 men) were included in the analysis for the discovery population. From a total of 76 734 calls to emergency medical services, 1171 patients (mean age 61·8 [SD 17·3] years; 643 women, 514 men, and 14 participants without data for sex) were included in the control group. Patients with sudden cardiac arrest were more likely to have dyspnoea (168 [41%] of 411 vs 262 [22%] of 1171; p<0·0001), chest pain (136 [33%] vs 296 [25%]; p=0·0022), diaphoresis (50 [12%] vs 90 [8%]; p=0·0059), and seizure-like activity (43 [11%] vs 77 [7%], p=0·011). Symptom frequencies and patterns differed significantly by sex. Among men, chest pain (odds ratio [OR] 2·2, 95% CI 1·6-3·0), dyspnoea (2·2, 1·6-3·0), and diaphoresis (1·7, 1·1-2·7) were significantly associated with sudden cardiac arrest, whereas among women, only dyspnoea was significantly associated with sudden cardiac arrest (2·9, 1·9-4·3). 427 patients with sudden cardiac arrest (mean age 62·2 [SD 13·5]; 122 women and 305 men) were included in the analysis for the replication population and 1238 patients (mean age 59·3 [16·5] years; 689 women, 548 men, and one participant missing data for sex) were included in the control group. Findings were mostly consistent in the replication population; however, notable differences included that, among men, diaphoresis was not associated with sudden cardiac arrest and chest pain was associated with sudden cardiac arrest only in the sex-stratified multivariable analysis. INTERPRETATION: The prevalence of warning symptoms was sex-specific and differed significantly between patients with sudden cardiac arrest and controls. Warning symptoms hold promise for prediction of imminent sudden cardiac arrest but might need to be augmented with additional features to maximise predictive power. FUNDING: US National Heart Lung and Blood Institute.

Presurgical 68Ga-PSMA-11 Positron Emission Tomography for Biochemical Recurrence Risk Assessment: A Follow-up Analysis of a Multicenter Prospective Phase 3 Imaging Trial.

BACKGROUND: In the initial staging of patients with high-risk prostate cancer (PCa), prostate-specific membrane antigen positron emission tomography (PSMA-PET) has been established as a front-line imaging modality. The increasing number of PSMA-PET scans performed in the primary staging setting might be associated with decreases in biochemical recurrence (BCR)-free survival (BCR-FS). OBJECTIVE: To assess the added prognostic value of presurgical PSMA-PET for BCR-FS compared with the presurgical Cancer of the Prostate Risk Assessment (CAPRA) and postsurgical CAPRA-Surgery (CAPRA-S) scores in patients with intermediate- to high-risk PCa treated with radical prostatectomy (RP) and pelvic lymph node dissection. DESIGN, SETTING, AND PARTICIPANTS: This is a follow-up study of the surgical cohort evaluated in the multicenter prospective phase 3 imaging trial (n = 277; NCT03368547, NCT02611882, and NCT02919111). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Each 68Ga-PSMA-11-PET scan was read by three blinded independent readers. PSMA-PET prostate uptake (low vs high), PSMA-PET extraprostatic disease (N1/M1), and CAPRA and CAPRA-S scores were used to assess the risk of BCR. Patients were followed after RP by local investigators using electronic medical records. BCR was defined by a prostate-specific antigen (PSA) level increasing to ≥0.2 ng/ml after RP or initiation of PCa-specific secondary treatment (>6 mo after surgery). Univariate and multivariable Cox models, and c-statistic index were performed to assess the prognostic value of PSMA-PET and for a comparison with the CAPRA and CAPRA-S scores. RESULTS AND LIMITATIONS: From December 2015 to December 2019, 277 patients underwent surgery after PSMA-PET. Clinical follow-up was obtained in 240/277 (87%) patients. The median follow-up after surgery was 32.4 (interquartile range 23.3-42.9) mo. Of 240 BCR events, 91 (38%) were observed. PSMA-PET N1/M1 was found in 41/240 (17%) patients. PSMA-PET prostate uptake, PSMA-PET N1/M1, and CAPRA and CAPRA-S scores were significant univariate predictors of BCR. The addition of PSMA-PET N1/M1 status to the presurgical CAPRA score improved the risk assessment for BCR significantly in comparison with the presurgical CAPRA score alone (c-statistic 0.70 [0.64-0.75] vs 0.63 [0.57-0.69]; p < 0.001). The C-index of the postsurgical model utilizing the postsurgical CAPRA-S score alone was not significantly different from the presurgical model combining the presurgical CAPRA score and PSMA-PET N1/M1 status (p = 0.19). CONCLUSIONS: Presurgical PSMA-PET was a strong prognostic biomarker improving BCR-FS risk assessment. Its implementation in the presurgical risk assessment with the CAPRA score improved the performance and reduced the difference with the reference standard (postsurgical CAPRA-S score). PATIENT SUMMARY: The use prostate-specific membrane antigen positron emission tomography improved the assessment of biochemical recurrence risk in patients with intermediate- and high-risk prostate cancer who were treated with radical prostatectomy and pelvic lymph node dissection.

Interplay of Cortisol, Testosterone, and Abdominal Fat Mass in Normal-weight Women With Polycystic Ovary Syndrome.

Context: Ovarian and adrenal steroidogenesis underlie endocrine-metabolic dysfunction in polycystic ovary syndrome (PCOS). Adipocytes express aldo-keto reductase 1C3 and type 1 11ß-hydroxysteroid dehydrogenase, which modulate peripheral androgen and cortisol production. Objectives: To compare serum adrenal steroids, including 11-oxygenated androgens (11-oxyandrogens), cortisol, and cortisone between normal-weight women with PCOS and body mass index- and age-matched ovulatory women with normal-androgenic profiles (controls), and assess whether adrenal steroids associate with abdominal adipose deposition. Design: Prospective, cross-sectional, cohort study. Setting: Academic medical center. Patients: Twenty normal-weight women with PCOS and 20 body mass index-/age-matched controls. Interventions: Blood sampling, IV glucose tolerance testing, and total-body dual-energy x-ray absorptiometry. Main Outcome Measures: Clinical characteristics, hormonal concentrations, and body fat distribution. Results: Women with PCOS had higher serum total/free testosterone (T) and androstenedione (A4) levels and a greater android/gynoid fat mass than controls (androgens P < .001; android/gynoid fat mass ratio, P = .026). Serum total/free T and A4 levels correlated positively with android/gynoid fat mass ratio in all women combined (P < .025, all values). Serum 11ß-hydroxyA4, 11-ketoA4, 11ß-hydroxyT, 11-ketoT, cortisol, and cortisone levels were comparable between female types and unrelated to body fat distribution. Serum 11-oxyandrogens correlated negatively with % total body fat, but lost significance adjusting for cortisol. Serum cortisol levels, however, correlated inversely with android fat mass (P = .021), with a trend toward reduced serum cortisol to cortisone ratio in women with PCOS vs controls (P = .075), suggesting diminished 11ß-hydroxysteroid dehydrogenase activity. Conclusion: Reduced cortisol may protect against preferential abdominal fat mass in normal-weight PCOS women with normal serum 11-oxyandrogens.

A Pilot Single-Site Randomized Control Trial: Investigating the Use of Donor Milk in the Late Preterm and Term Infant in the Neonatal Intensive Care Unit.

Objective : We aimed to study the use of donor milk (DM) in term and late preterm infants (LPIs) when mother’s own milk (MOM) was unavailable. We hypothesized this study would be feasible and breastfeeding attempts and the percentage of MOM (MOM%) would increase with DM without adversely affecting growth. Study Design : This was a pilot study (n=32). Infants with gestational age >34 weeks admitted to the neonatal intensive care unit were included. Infants were randomized to: the human milk (MOM+DM) or formula (MOM+F) groups. Result : Consent rate was 52%. Breastfeeding attempts increased significantly over time in the MOM+DM group compared to the MOM+F group (group p=0.41, time p =0.02, group*time p=0.01) . Growth at multiple time points was similar when the two groups were compared. Conclusion : A study randomizing term infants and LPIs to DM or formula when MOM is unavailable is feasible. DM may increase breastfeeding attempts without compromising growth.

68Ga-PSMA PET/CT-Based Atlas for Prostate Bed Recurrence After Radical Prostatectomy: Clinical Implications for Salvage Radiation Therapy Contouring Guidelines.

The aim of this study was to analyze the patterns of prostate bed (PB) recurrence in prostate cancer patients experiencing prostate-specific antigen (PSA) persistence (BCP) or biochemical recurrence (BCR) after radical prostatectomy using 68Ga-PSMA-11 PET/CT (68Ga-PSMA PET) in relation to the Radiation Therapy Oncology Group (RTOG) clinical target volumes (CTVs). Methods: This single-center, retrospective analysis included patients with BCP or BCR after radical prostatectomy and PB recurrence on 68Ga-PSMA PET. The PB recurrences were delineated by nuclear medicine physicians, the CTVs by radiation oncologists contouring guidelines on the 68Ga-PSMA PET, respectively, masked from each other. The coverage of the 68Ga-PSMA PET recurrence was categorized as PSMA recurrence completely covered, partially covered, or not covered by the RTOG-based CTV. Further, we evaluated the differences in PSMA recurrence patterns among patients with different 68Ga-PSMA PET staging (miTNM). Mann-Whitney U tests, the chi-square test, and Spearman (ρ) correlation analysis were used to investigate associations between CTV coverage and 68Ga-PSMA PET-based tumor volume, serum PSA levels, miTNM, and rectal/bladder involvement. Results: A total of 226 patients were included in the analysis; 127 patients had PSMA recurrence limited to the PB (miTrN0M0), 30 had pelvic nodal disease (miTrN1M0), 32 had extrapelvic disease (miTrN0M1), and 37 had both pelvic nodal disease and extrapelvic disease (miTrN1M1). In the miTrN0M0 cohort, the recurrence involved the rectal and bladder walls in 12 of 127 (9%) and 4 of 127 (3%), respectively. The PSMA-positive PB recurrences were completely covered by the CTV in 68 of 127 patients (53%), partially covered in 43 of 127 (34%), and not covered in 16 of 127 (13%). Full coverage was associated with a smaller tumor volume (P = 0.043), a lack of rectal/bladder wall involvement (P = 0.03), and lower miTNM staging (P = 0.035) but not with lower serum PSA levels (P = 0.979). Conclusion: Our study suggests that 68Ga-PSMA PET can be a valuable tool for guiding salvage radiation therapy (SRT) planning directed to the PB in the setting of postoperative BCR or BCP. These data should be incorporated into the redefinition of PB contouring guidelines.