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.

Preoperative Point-of-Care Ultrasound to Identify Frailty and Predict Postoperative Outcomes: A Diagnostic Accuracy Study.

BACKGROUND: Frailty is increasingly being recognized as a public health issue, straining healthcare resources and increasing costs to care for these patients. Frailty is the decline in physical and cognitive reserves leading to increased vulnerability to stressors such as surgery or disease states. The goal of this pilot diagnostic accuracy study was to identify whether point-of-care ultrasound measurements of the quadriceps and rectus femoris muscles can be used to discriminate between frail and not-frail patients and predict postoperative outcomes. This study hypothesized that ultrasound could discriminate between frail and not-frail patients before surgery. METHODS: Preoperative ultrasound measurements of the quadriceps and rectus femoris were obtained in patients with previous computed tomography scans. Using the computed tomography scans, psoas muscle area was measured in all patients for comparative purposes. Frailty was identified using the Fried phenotype assessment. Postoperative outcomes included unplanned intensive care unit admission, delirium, intensive care unit length of stay, hospital length of stay, unplanned skilled nursing facility admission, rehospitalization, falls within 30 days, and all-cause 30-day and 1-yr mortality. RESULTS: A total of 32 patients and 20 healthy volunteers were included. Frailty was identified in 18 of the 32 patients. Receiver operating characteristic curve analysis showed that quadriceps depth and psoas muscle area are able to identify frailty (area under the curve-receiver operating characteristic, 0.80 [95% CI, 0.64 to 0.97] and 0.88 [95% CI, 0.76 to 1.00], respectively), whereas the cross-sectional area of the rectus femoris is less promising (area under the curve-receiver operating characteristic, 0.70 [95% CI, 0.49 to 0.91]). Quadriceps depth was also associated with unplanned postoperative skilled nursing facility discharge disposition (area under the curve 0.81 [95% CI, 0.61 to 1.00]) and delirium (area under the curve 0.89 [95% CI, 0.77 to 1.00]). CONCLUSIONS: Similar to computed tomography measurements of psoas muscle area, preoperative ultrasound measurements of quadriceps depth shows promise in discriminating between frail and not-frail patients before surgery. It was also associated with skilled nursing facility admission and postoperative delirium.

Relationship Between the Anion Gap and Serum Lactate in Hypovolemic Shock.

Background and objectives: Previous studies evaluating patients in the Intensive Care Unit with established lactic acidosis determined that the anion gap is an insensitive screening tool for elevated blood lactate. No prior study has examined the relationship between anion gap and serum lactate within the first hours of the development of lactic acidosis. Design, setting, participants, & measurements: Data were obtained prospectively from a convenience sample of adult trauma patients at a single level 1 trauma center. Venous samples were drawn prior to initiation of intravenous fluid resuscitation. A linear regression model was constructed to assess the relationship between serum lactate and anion gap, and 95% prediction intervals were computed. Logistic regression models were constructed to determine the sensitivity and specificity for several different anion gap and lactate cutpoints. Results: 128 patients with elevated serum lactate levels (>2.1 mmol/L) and 63 patients with normal serum lactate levels (< 2.1 mmol/L) were included. The sensitivity of an elevated anion gap (> 10) to reveal hyperlactatemia was only 43% whereas specificity was 84%. Sensitivity improved if the upper limit of normal anion gap was lowered and with increasing levels of serum lactate. The coefficient of determination between serum lactate level and AG yielded an R2 of 0.30 (p < 0.001) and the slope of this relationship was 2.185 with a 95% confidence interval of 2.011-2.359. The mean 95% prediction interval was + 8.9. Conclusions: Within the first hour of the development of lactic acidosis due to hypovolemic shock, the anion gap was not a sensitive indicator of an elevated serum lactate level, but it was fairly specific. The anion gap increased to a greater extent than the serum lactate, the 95% mean prediction interval was wide and approximately 70% of the change in anion gap could not be explained by increases in serum lactate, suggesting that other anions contribute to the anion gap in lactic acidosis.

Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

Accuracy of administrative database estimates of national surgical volume: Solid organ transplantation in the National Inpatient Sample.

BACKGROUND: Little is known about the accuracy of procedural coding in the National Inpatient Sample, in part because it is challenging to validate population-level estimates. METHODS: We evaluated the accuracy of the National Inpatient Sample by comparing estimates of solid organ transplantation to known national transplant volumes from the Organ Procurement and Transplant Network. RESULTS: The mean deviation of National Inpatient Sample point estimates from true transplant volume for the study period was 17.5 ± 20.8%. The mean deviation of point estimates from 2005 to 2011 was 26.4 ± 22.8% compared to 4.9 ± 6.3% from 2012 to 2016 (P < .001). CONCLUSIONS: Although future National Inpatient Sample transplantation research may be limited by the inability to subgroup procedures by donor type, surgical procedure coding of solid organ transplantation within the National Inpatient Sample appears to be accurate and reliable for generating national estimates, particularly after the National Inpatient Sample redesign in 2012.

Combined Percutaneous Tracheostomy and Endoscopic Gastrostomy Tubes in COVID-19: A Prospective Series of Patient Outcomes.

Background: A significant number of patients with severe respiratory failure related to COVID-19 require prolonged mechanical ventilation. Minimal data exists regarding the timing, safety, and efficacy of combined bedside percutaneous tracheostomy and endoscopy gastrostomy tube placement in these patients. The safety for healthcare providers is also in question. This study's objective was to evaluate the effectiveness and safety of combined bedside tracheostomy and gastrostomy tube placement in COVID-19 patients. Design and Methods: This is a single arm, prospective cohort study in patients with COVID-19 and acute respiratory failure requiring prolonged mechanical ventilation who underwent bedside tracheostomy and percutaneous endoscopic gastrostomy placement. Detailed clinical and procedural data were collected. Descriptive statistics were employed and time to event curves were estimated and plotted using the Kaplan Meier method for clinically relevant prespecified endpoints. Results: Among 58 patients, the median total intensive care unit (ICU) length of stay was 29 days (24.7-33.3) with a median of 10 days (6.3-13.7) postprocedure. Nearly 88% of patients were weaned from mechanical ventilation postprocedure at a median of 9 days (6-12); 94% of these were decannulated. Sixty-day mortality was 10.3%. Almost 90% of patients were discharged alive from the hospital. All procedures were done at bedside with no patient transfer required out of the ICU. A median of 3.0 healthcare personnel total were present in the room per procedure. Conclusion: This study shows that survival of critically ill COVID-19 patients after tracheostomy and gastrostomy was nearly 90%. The time-to-event curves are encouraging regarding time to weaning, downsizing, decannulation, and discharge. A combined procedure minimizes the risk of virus transmission to healthcare providers in addition to decreasing the number of anesthetic episodes, transfusions, and transfers patients must undergo. This approach should be considered in critically ill COVID-19 patients requiring prolonged mechanical ventilation.

Loss of anti-Müllerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classical polycystic ovary syndrome (PCOS).

Anti-Müllerian hormone (AMH) is produced by granulosa cells of pre-antral and small antral ovarian follicles. In polycystic ovary syndrome (PCOS), higher levels of serum AMH are usually encountered due to the ample presence of small antral follicles and a high AMH production per follicular unit which have led to the proposal of AMH as a serum diagnostic marker for PCOS or as a surrogate for polycystic ovarian morphology (PCOM). However, heterozygous coding mutations of the AMH gene with decreased in vitro bioactivity have been described in some women with PCOS. Such mutation carriers have a trend toward reduced serum AMH levels compared to noncarriers, although both types of women with PCOS have similar circulating gonadotropin and testosterone (T) levels. This report describes a normal-weight woman with PCOS by NIH criteria with severely reduced AMH levels (index woman with PCOS). Our objective was to examine the molecular basis for her reduced serum AMH levels and to compare her endocrine characteristics to similar-weight women with PCOS and detectable AMH levels. Twenty normoandrogenic ovulatory (control) and 13 age- and BMI-matched women with PCOS (19-35 years; 19-25 kg/m2) underwent transvaginal sonography and serum hormone measures including gonadotropins, sex hormone-binding globulin, total and free T, androstenedione, dehydroepiandrosterone sulfate, estrone, estradiol and AMH. The latter was measured by ELISA (Pico-AMH: Ansh Labs, Webster, TX, USA). Women with PCOS and detectable AMH had higher serum AMH (10.82 (6.74-13.40) ng/ml, median (interquartile range)), total and free T (total T: 55.5 (49.5-62.5) ng/dl; free T: 5.65 (4.75-6.6) pg/ml) levels and greater total antral follicle count (AFC) (46 (39-59) follicles) than controls (AMH: 4.03 (2.47-6.11) ng/ml; total T: 30 (24.5-34.5) ng/dl; free T: 2.2 (1.8-2.45) pg/ml; AFC 16 (14.5-21.5) follicles, P < 0.05, all values), along with a trend toward LH hypersecretion (P = 0.06). The index woman with PCOS had severely reduced serum AMH levels (∼0.1 ng/ml), although she also had a typical NIH-defined PCOS phenotype resembling that of the other women with PCOS and elevated AMH levels. All women with PCOS, including the index woman with PCOS, exhibited LH hypersecretion, hyperandrogenism, reduced serum estrogen/androgen ratios and PCOM. A homozygous Ala515Val variant (rs10417628) in the mature region of AMH was identified in the index woman with PCOS. Recombinant hAMH-515Val displayed normal processing and bioactivity, yet had severely reduced immunoactivity when measured by the commercial pico-AMH ELISA assay by Ansh Labs. In conclusion, homozygous AMH variant rs10417628 may severely impair serum AMH immunoactivity without affecting its bioactivity or PCOS phenotypic expression. Variants in AMH can interfere with serum AMH immunoactivity without affecting the phenotype in PCOS. This observation can be accompanied by discordance between AMH immunoactivity and bioactivity.

Assessing Acid-Base Status in Circulatory Failure: Relationship Between Arterial and Peripheral Venous Blood Gas Measurements in Hypovolemic Shock.

BACKGROUND AND OBJECTIVES: In severe circulatory failure agreement between arterial and mixed venous or central venous values is poor; venous values are more reflective of tissue acid-base imbalance. No prior study has examined the relationship between peripheral venous blood gas (VBG) values and arterial blood gas (ABG) values in hemodynamic compromise. The objective of this study was to examine the correlation between hemodynamic parameters, specifically systolic blood pressure (SBP) and the arterial-peripheral venous (A-PV) difference for all commonly used acid-base parameters (pH, Pco 2, and bicarbonate). DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Data were obtained prospectively from adult patients with trauma. When an ABG was obtained for clinical purposes, a VBG was drawn as soon as possible. Patients were excluded if the ABG and VBG were drawn >10 minutes apart. RESULTS: The correlations between A-PV pH, A-PV Pco 2, and A-PV bicarbonate and SBP were not statistically significant (P = .55, .17, and .09, respectively). Although patients with hypotension had a lower mean arterial and peripheral venous pH and bicarbonate compared to hemodynamically stable patients, mean A-PV differences for pH and Pco 2 were not statistically different (P = .24 and .16, respectively) between hypotensive and normotensive groups. CONCLUSIONS: In hypovolemic shock, the peripheral VBG does not demonstrate a higher CO2 concentration and lower pH compared to arterial blood. Therefore, the peripheral VBG is not a surrogate for the tissue acid-base status in hypovolemic shock, likely due to peripheral vasoconstriction and central shunting of blood to essential organs. This contrasts with the selective venous respiratory acidosis previously demonstrated in central venous and mixed venous measurements in circulatory failure, which is more reflective of acid-base imbalance at the tissue level than arterial blood. Further work needs to be done to better define the relationship between ABG and both central and peripheral VBG values in various types of shock.

PD-1 blockade induces responses by inhibiting adaptive immune resistance.

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.

Physical symptoms and psychosocial problems associated with hidradenitis suppurativa: correlation with Hurley stage.

BACKGROUND: Quality of life (QOL) in hidradenitis suppurativa (HS) patients is negatively impacted by physical and psychosocial problems. The aim of this study was to investigate the frequency and severity of HS-specific symptoms and to correlate these with disease severity. Methods We analyzed medical record data from 145 patients seen in an academic HS specialty clinic between August 2009 to March 2018. Results Hurley stage III patients had significantly higher mean Dermatology Life Quality Index (DLQI) scores (20.2) compared to patients with Hurley stage I (11.3) and II (13.9), (P<0.001 and P=0.001, respectively). More than 75% of patients reported physical symptoms of drainage, irritation, pain, itching, bleeding, and odor. There were associated psychosocial problems of embarrassment and self-consciousness. Symptom severity was most strongly correlated with disease severity for odor (correlation coefficient 0.4, P<0.001), difficulty moving arms (0.323, P<0.001), negative impact on job/school (0.303, P<0.001), and negative impact on relationships (0.298, P<0.001). Conclusion Our results highlight the significant burden of HS and the need for a more comprehensive, HS-specific evaluation tool to better assess the QOL of this patient population. Limitations A small cohort in a single academic center.

Regional Left Ventricular Myocardial Dysfunction After Cardiac Surgery Characterized by 3-Dimensional Strain.

BACKGROUND: Three-dimensional (3D) strain is an echocardiographic modality that can characterize left ventricular (LV) function with greater accuracy than ejection fraction. While decreases in global strain have been used to predict outcomes after cardiac surgery, changes in regional 3D longitudinal, circumferential, radial, and area strain have not been well described. The primary aim of this study was to define differential patterns in regional LV dysfunction after cardiac surgery using 3D speckle tracking strain imaging. Our secondary aim was to investigate whether changes in regional strain can predict postoperative outcomes, including length of intensive care unit stay and 1-year event-free survival. METHODS: In this prospective clinical study, demographic, operative, echocardiographic, and clinical outcome data were collected on 182 patients undergoing aortic valve replacement, mitral valve repair or replacement, coronary artery bypass graft, and combined cardiac surgery. Three-dimensional transthoracic echocardiograms were performed preoperatively and on the second to fourth postoperative day. Blinded analysis was performed for LV regional longitudinal, circumferential, radial, and area strain in the 17-segment model. RESULTS: Regional 3D longitudinal, circumferential, radial, and area strains were associated with differential patterns of myocardial dysfunction, depending on the surgical procedure performed and strain measure. Patients undergoing mitral valve repair or replacement had reduced function in the majority of myocardial segments, followed by coronary artery bypass graft, while patients undergoing aortic valve replacement had reduced function localized only to apical segments. After all types of cardiac surgery, segmental function in apical segments was reduced to a greater extent as compared to basal segments. Greater decrements in regional function were seen in circumferential and area strain, while smaller decrements were observed in longitudinal strain in all surgical patients. Both preoperative regional strain and change in regional strain preoperatively to postoperatively were correlated with reduced 1-year event-free survival, while postoperative strain was not predictive of outcomes. Only preoperative strain values were predictive of intensive care unit length of stay. CONCLUSIONS: Changes in regional myocardial function, measured by 3D strain, varied by surgical procedure and strain type. Differences in regional LV function, from presurgery to postsurgery, were associated with worsened 1-year event-free survival. These findings suggest that postoperative changes in myocardial function are heterogeneous in nature, depending on the surgical procedure, and that these changes may have long-term impacts on outcome. Therefore, 3D regional strain may be used to identify patients at risk for worsened postoperative outcomes, allowing early interventions to mitigate risk.

Retrospective Cohort Study on the Optimal Timing of Orogastric Tube/Nasogastric Tube Insertion in Infants With Pyloric Stenosis.

BACKGROUND: Hypertrophic pyloric stenosis in infants can cause a buildup of gastric contents. Orogastric tubes (OGTs) or nasogastric tubes (NGTs) are often placed in patients with pyloric stenosis before surgical management to prevent aspiration. However, exacerbation of gastric losses may lead to electrolyte abnormalities that can delay surgery, and placement has been associated with increased risk of postoperative emesis. Currently, there are no evidence-based guidelines regarding OGT/NGT placement in these patients. This study examines whether OGT/NGT placement before arrival in the operating room was associated with a longer time to readiness for surgery as defined by normalization of electrolytes. Secondary outcomes included time from surgery to discharge and ability to tolerate feeds by 6 hours postoperatively in patients with and without early OGT/NGT placement. METHODS: In this multicenter retrospective cohort study, data were extracted from the medical records of 481 patients who underwent pyloromyotomy for infantile hypertrophic pyloric stenosis from March 2013 to June 2016. Multivariable linear regression and Cox proportional hazard models were constructed to evaluate the association between placement of an OGT/NGT at the time of admission with increased time to readiness for surgery (defined as the time from admission to the first set of normalized laboratory values) and increased time from surgery to discharge. Multivariable logistic regression was used to evaluate the association between early OGT/NGT placement and the ability to tolerate oral intake at 6 hours postsurgery. Analyses were adjusted for site differences. RESULTS: Among patients admitted with electrolyte abnormalities, those with an OGT/NGT placed on presentation required more time until their serum electrolytes were at acceptable levels for surgery by regression analysis (19.2 hours difference; 95% confidence interval, 10.05-28.41; P < .001), after adjusting for site. Overall, patients who had OGTs/NGTs placed before presentation in the operating room had a longer length of stay from surgery to discharge than those without (38.8 hours difference; 95% confidence interval, 25.35-52.31; P < .001), after adjusting for site. OGT/NGT placement before surgery was not associated with failure to tolerate oral intake within 6 hours of surgery after adjusting for site, corrected gestational age, and baseline serum electrolytes. CONCLUSIONS: OGT/NGT placement on admission for pyloric stenosis is associated with a longer time to electrolyte correction in infants with abnormal laboratory values on presentation and, subsequently, a longer time until they are ready for surgery. It is also associated with longer postoperative hospital stay but not an increased risk of feeding intolerance within 6 hours of surgical repair.

Characterization of Human Salivary Extracellular RNA by Next-generation Sequencing.

BACKGROUND: It was recently discovered that abundant and stable extracellular RNA (exRNA) species exist in bodily fluids. Saliva is an emerging biofluid for biomarker development for noninvasive detection and screening of local and systemic diseases. Use of RNA-Sequencing (RNA-Seq) to profile exRNA is rapidly growing; however, no single preparation and analysis protocol can be used for all biofluids. Specifically, RNA-Seq of saliva is particularly challenging owing to high abundance of bacterial contents and low abundance of salivary exRNA. Given the laborious procedures needed for RNA-Seq library construction, sequencing, data storage, and data analysis, saliva-specific and optimized protocols are essential. METHODS: We compared different RNA isolation methods and library construction kits for long and small RNA sequencing. The role of ribosomal RNA (rRNA) depletion also was evaluated. RESULTS: The miRNeasy Micro Kit (Qiagen) showed the highest total RNA yield (70.8 ng/mL cell-free saliva) and best small RNA recovery, and the NEBNext library preparation kits resulted in the highest number of detected human genes [5649-6813 at 1 reads per kilobase RNA per million mapped (RPKM)] and small RNAs [482-696 microRNAs (miRNAs) and 190-214 other small RNAs]. The proportion of human RNA-Seq reads was much higher in rRNA-depleted saliva samples (41%) than in samples without rRNA depletion (14%). In addition, the transfer RNA (tRNA)-derived RNA fragments (tRFs), a novel class of small RNAs, were highly abundant in human saliva, specifically tRF-4 (4%) and tRF-5 (15.25%). CONCLUSIONS: Our results may help in selection of the best adapted methods of RNA isolation and small and long RNA library constructions for salivary exRNA studies.

Discovery and Validation of Salivary Extracellular RNA Biomarkers for Noninvasive Detection of Gastric Cancer.

BACKGROUND: Biomarkers are needed for noninvasive early detection of gastric cancer (GC). We investigated salivary extracellular RNA (exRNA) biomarkers as potential clinical evaluation tools for GC. METHODS: Unstimulated whole saliva samples were prospectively collected from 294 individuals (163 GC and 131 non-GC patients) who underwent endoscopic evaluation at the Samsung Medical Center in Korea. Salivary transcriptomes of 63 GC and 31 non-GC patients were profiled, and mRNA biomarker candidates were verified with reverse transcription quantitative real-time PCR (RT-qPCR). In parallel, microRNA (miRNA) biomarkers were profiled and verified with saliva samples from 10 GC and 10 non-GC patients. Candidate biomarkers were validated with RT-qPCR in an independent cohort of 100/100 saliva samples from GC and non-GC patients. Validated individual markers were configured into a best performance panel. RESULTS: We identified 30 mRNA and 15 miRNA candidates whose expression pattern associated with the presence of GC. Among them, 12 mRNA and 6 miRNA candidates were verified with the discovery cohort by RT-qPCR and further validated with the independent cohort (n = 200). The configured biomarker panel consisted of 3 mRNAs (SPINK7, PPL, and SEMA4B) and 2 miRNAs (MIR140-5p and MIR301a), which were all significantly down-regulated in the GC group, and yielded an area under the ROC curve (AUC) of 0.81 (95% CI, 0.72-0.89). When combined with demographic factors, the AUC of the biomarker panel reached 0.87 (95% CI, 0.80-0.93). CONCLUSIONS: We have discovered and validated a panel of salivary exRNA biomarkers with credible clinical performance for the detection of GC. Our study demonstrates the potential utility of salivary exRNA biomarkers in screening and risk assessment for GC.

Salivary exRNA biomarkers to detect gingivitis and monitor disease regression.

AIM: This study tests the hypothesis that salivary extracellular RNA (exRNA) biomarkers can be developed for gingivitis detection and monitoring disease regression. MATERIALS AND METHODS: Salivary exRNA biomarker candidates were developed from a total of 100 gingivitis and non-gingivitis individuals using Affymetrix's expression microarrays. The top 10 differentially expressed exRNAs were tested in a clinical cohort to determine whether the discovered salivary exRNA markers for gingivitis were associated with clinical gingivitis and disease regression. For this purpose, unstimulated saliva was collected from 30 randomly selected gingivitis subjects, the gingival and plaque indexes scores were taken at baseline, 3 and 6 weeks and salivary exRNAs were assayed by means of reverse transcription quantitative polymerase chain reaction. RESULTS: Eight salivary exRNA biomarkers developed for gingivitis were statistically significantly changed over time, consistent with disease regression. A panel of four salivary exRNAs [SPRR1A, lnc-TET3-2:1, FAM25A, CRCT1] can detect gingivitis with a clinical performance of 0.91 area under the curve, with 71% sensitivity and 100% specificity. CONCLUSIONS: The clinical values of the developed salivary exRNA biomarkers are associated with gingivitis regression. They offer strong potential to be advanced for definitive validation and clinical laboratory development test.

Does A Low 6-Minute Walk Distance Predict Elevated Postoperative Troponin?

Our study of 100 major vascular and renal transplant patients evaluated the 6-minute walk test (6MWT) as an indicator of perioperative myocardial injury, using troponin as a marker. Using logistic regression and the area under the receiving operator characteristic curve, we compared the 6MWT to the Revised Cardiac Risk Index and metabolic equivalents. Only the 6MWT was associated with elevated postoperative troponins (95% CI, 0.98-0.99). However, the 6MWT area under the receiving operator characteristic curve (0.71 [95% CI, 0.57-0.85]) was not different from the Revised Cardiac Risk Index (P = .23) or metabolic equivalents (P = .14). The 6MWT may have a role in cardiac risk stratification in the perioperative setting.

Increased Central Nervous System Interleukin-8 in a Majority Postlaminectomy Syndrome Chronic Pain Population.

Background and Objectives: Multiple processes have been identified as potential contributors to chronic pain, with increasing evidence illustrating an association with aberrant levels of neuroimmune mediators. The primary objectives of the present study were to examine central nervous system cytokines, chemokines, and growth factors present in a chronic pain population and to explore patterns of the same mediator molecules over time. Secondary objectives explored the relationship of central and peripheral neuroimmune mediators while examining the levels of anxiety, depression, sleep quality, and perception of pain associated with the chronic pain patient experience. Methods: Cerebrospinal fluid (CSF) from a population of majority postlaminectomy syndrome patients (N = 8) was compared with control CSF samples (N = 30) to assess for significant differences in 10 cytokines, chemokines, and growth factors. The patient population was then followed over time, analyzing CSF, plasma, and psychobehavioral measures. Results: The present observational study is the first to demonstrate increased mean CSF levels of interleukin-8 (IL-8; P < 0.001) in a small population of majority postlaminectomy syndrome patients, as compared with a control population. Over time in pain patients, CSF levels of IL-8 increased significantly (P < 0.001). Conclusions: These data indicate that IL-8 should be further investigated and psychobehavioral components considered in the overall chronic pain paradigm. Future studies examining the interactions between these factors and IL-8 may identify novel targets for treatment of persistent pain states.

A comparison of postoperative outcomes with PDA ligation in the OR versus the NICU: a retrospective cohort study on the risks of transport.

BACKGROUND: Although patent ductus arteriosus (PDA) ligations in the Neonatal Intensive Care Unit (NICU) have been an accepted practice, many are still performed in the Operating Room (OR). Whether avoiding transport leads to improved perioperative outcomes is unclear. Here we aimed to determine whether PDA ligations in the NICU corresponded to higher risk of surgical site infection or mortality and if transport was associated with worsened perioperative outcomes. METHODS: We performed a retrospective cohort study of NICU patients, ≤37 weeks post-menstrual age, undergoing surgical PDA ligation in the NICU or OR. We excluded any infants undergoing device PDA closure. We measured the incidence of perioperative hypothermia, cardiac arrest, decreases in SpO2, hemodynamic instability and postoperative surgical site infection, sepsis and mortality. RESULTS: Data was collected on 189 infants (100 OR, 89 NICU). After controlling for number of preoperative comorbidities, weight at time of procedure, procedure location and hospital in the mixed-effect model, no significant difference in mortality or sepsis was found (odds ratio 0.31, 95%CI 0.07, 1.30; p = 0.107, and odds ratio 0.40; 95%CI 0.14, 1.09; p = 0.072, respectively). There was an increased incidence of hemodynamic instability on transport postoperatively in the OR group (12.4% vs 2%, odds ratio 6.93; 95% CI 1.48, 35.52; p = 0.014). CONCLUSION: PDA ligations in the NICU were not associated with higher incidences of surgical site infection or mortality. There was an increased incidence of hemodynamic instability in the OR group on transport back to the NICU. Larger multicenter studies following long-term outcomes are needed to evaluate the safety of performing all PDA ligations in the NICU.

Perioperative respiratory adverse event risk assessment in children with upper respiratory tract infection: Validation of the COLDS score.

BACKGROUND: The decision to proceed with anesthesia and surgery has been controversial in pediatric patients with an upper respiratory tract infection. The COLDS score was proposed by Lee and August as a potential risk stratification scheme, but no validation has been performed on this scale. AIMS: The aim of this study was to evaluate the utility of the COLDS score in predicting perioperative respiratory adverse events and optimize its predictive ability. METHODS: COLDS scores, incidence of perioperative respiratory adverse events, surgical procedure type, and age were prospectively collected for 536 patients who met inclusion criteria. Area under the receiver operating characteristic curves was computed for total COLDS score and individual COLDS score categories. Multivariable regression was used create an optimized score. To quantify the decrease in risk associated with case cancelation due to illness, the other risk factors in COLDS were assessed separately from upper respiratory infection status and a risk model was created. RESULTS: The area under the receiver operating characteristic curve for the total COLDS score was 0.69, suggesting that the COLDS score has a moderate predictive ability for perioperative respiratory adverse events. When split into individual component scores, the area under the receiver operating characteristic curve ranged from 0.55 to 0.63. We also found that the area under the receiver operating characteristic curve for the scoring system was higher in younger children than for children aged 4-6 (area under receiver operating characteristic curve of 0.70-0.71 vs 0.66). The area under the receiver operating characteristic curve for the optimized scoring system was 0.71. CONCLUSION: The COLDS score has the potential to be a valuable risk assessment tool for prediction of perioperative respiratory adverse events and appears to have a better predictive value in certain subpopulations.

Non-small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges.

BACKGROUND: Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated. METHODS: The authors retrospectively reviewed data generated by patients who consented to 1 or more interventional lung cancer clinical trials at the University of California-Los Angeles Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment. RESULTS: In total, 311 patients underwent 368 screening incidents for 1 or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs 14 days) than trials that did not require a biopsy (P < .001). Trials that required a biopsy had a greater screen failure rate (49.1% vs 26.5%; P < .001), which was largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients. CONCLUSIONS: Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, these requirements lead to a lengthening of the screening period, which, in some patients, is associated with clinical decline before enrollment. Implications for the interpretation of data from studies of this design should be explored. Cancer 2017;123:4800-7. © 2017 American Cancer Society.