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Increasing antimicrobial resistance with Helicobacter pylori infection has focused efforts to tailor eradication therapy based on identifying genetic markers of resistance to predict antimicrobial susceptibility. In this retrospective study, we report the impact of routine inclusion of antimicrobial susceptibility testing and recommendations for eradication therapy with gastric specimens with H. pylori. The use of a recommended treatment regimen based on genetic markers of resistance was associated with an 84% rate of eradication success and 4.4 greater odds of eradication relative to unrecommended treatment. This is the first study describing use of H. pylori genetic resistance testing as standard of care.

Cardiovascular conditions such as hypertension, arrhythmias, and heart failure are common in patients undergoing anesthesia for surgical or other procedures. Numerous guidelines from various specialty societies offer variable recommendations for the perioperative management of these medications. The Society for Perioperative Assessment and Quality Improvement identified a need to provide multidisciplinary evidence-based recommendations for preoperative medication management. The society convened a group of 13 members with expertise in perioperative medicine and training in anesthesiology or internal medicine. The aim of this consensus effort is to provide perioperative clinicians with guidance on the management of cardiovascular medications commonly encountered during the preoperative evaluation. We used a modified Delphi process to establish consensus. Twenty-one classes of medications were identified: α-adrenergic receptor antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitors, β-adrenoceptor blockers, calcium-channel blockers, centrally acting sympatholytic medications, direct-acting vasodilators, loop diuretics, thiazide diuretics, potassium-sparing diuretics, endothelin receptor antagonists, cardiac glycosides, nitrodilators, phosphodiesterase-5 inhibitors, class III antiarrhythmic agents, potassium-channel openers, renin inhibitors, class I antiarrhythmic agents, sodium-channel blockers, and sodium glucose cotransportor-2 inhibitors. We provide recommendations for the management of these medications preoperatively.

Figure S1. AKT and ERK activity following increasing doses of BGJ398, GDC-0941, BYL719 and BKM120 in AN3CA and JHUEM2 cells.

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Supplementary Data from Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry

Purpose: More than 20 million archival tissue samples are stored annually in the United States as formalin-fixed, paraffin-embedded (FFPE) blocks, but RNA degradation during fixation and storage has prevented their use for transcriptional profiling. New and highly sensitive assays for whole-transcriptome microarray analysis of FFPE tissues are now available, but resulting data include noise and variability for which previous expression array methods are inadequate.Experimental Design: We present the two largest whole-genome expression studies from FFPE tissues to date, comprising 1,003 colorectal cancer (CRC) and 168 breast cancer samples, combined with a meta-analysis of 14 new and published FFPE microarray datasets. We develop and validate quality control (QC) methods through technical replication, independent samples, comparison to results from fresh-frozen tissue, and recovery of expected associations between gene expression and protein abundance.Results: Archival tissues from large, multicenter studies showed a much wider range of transcriptional data quality relative to smaller or frozen tissue studies and required stringent QC for subsequent analysis. We developed novel methods for such QC of archival tissue expression profiles based on sample dynamic range and per-study median profile. This enabled validated identification of gene signatures of microsatellite instability and additional features of CRC, and improved recovery of associations between gene expression and protein abundance of MLH1, FASN, CDX2, MGMT, and SIRT1 in CRC tumors.Conclusions: These methods for large-scale QC of FFPE expression profiles enable study of the cancer transcriptome in relation to extensive clinicopathological information, tumor molecular biomarkers, and long-term lifestyle and outcome data. Clin Cancer Res; 18(22); 6136–46. ©2012 AACR.

PDF file - 31K, Supplemental Table S1: Correlation between mRNA expression and status of protein expression, promoter CpG island methylation, or other tumor biomarker status.

PDF file - 1787K, Supplemental Figure S1: Immunohistochemistry for selected proteins. Supplemental Figure S2: Pairwise scatterplots of technical variables for 1,003 DASL arrays from the NHS/HPFS study, including median value of Illumina control probes, sample age, RNA concentration, fraction of probes called present (p

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families.Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing.Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups.Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking. Clin Cancer Res; 16(7); 2214–24. ©2010 AACR.

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Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n = 55) and mutation data (n = 20).Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%–90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P = 0.002/0.035), ER-negative (P = 0.02/0.02), and ERBB2-amplified tumors (P < 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P < 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P = 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P < 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res; 23(17); 5210–7. ©2017 AACR.

Figures S1 and S2, Tables S1 and S2 Supplementary Information Supplementary Table 1. DCIS cases assessed for tumour lymphocytes Supplementary Table 2. DCIS cases assessed for PD-L1 protein expression Supplementary Figure 1. Cohort summary Supplementary Figure 2. TILs in DCIS cases comparing primary with recurrence tumours.

Background: breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. Patients and methods: we included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 −5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 −4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. Conclusions: this is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Anesthesia assistance is commonly used for ERCP. General anesthesia (GA) may provide greater airway protection but may lead to hypotension. We aimed to compare GA versus sedation without planned intubation (SWPI) on the incidence of hypoxemia and hypotension. We also explored risk factors for conversion from SWPI to GA.This observational study used data from the Multicenter Perioperative Outcomes Group. Adults with American Society of Anesthesiologists physical status class I to IV undergoing ERCP between 2006 and 2019 were included. We compared GA and SWPI on incidence of hypoxemia (oxygen saturation 90% for ≥3 minutes) and hypotension (mean arterial pressure 65 mm Hg for ≥5 minutes) using joint hypothesis testing. The association between anesthetic approach and outcomes was assessed using logistic regression. The noninferiority delta for hypoxemia and hypotension was an odds ratio of 1.20. One approach was deemed better if it was noninferior on both outcomes and superior on at least 1 outcome. To explore risk factors associated with conversion from SWPI to GA, we constructed a logistic regression model.Among 61,735 cases from 42 institutions, 38,830 (63%) received GA and 22,905 (37%) received SWPI. The GA group had 1.27 times (97.5% confidence interval, 1.19-1.35) higher odds of hypotension but .71 times (97.5% confidence interval, .63-.80) lower odds of hypoxemia. Neither group was noninferior to the other on both outcomes. Conversion from SWPI to GA occurred in 6.5% of cases and was associated with baseline comorbidities and higher institutional procedure volume.GA for ERCP was associated with less hypoxemia, whereas SWPI was associated with less hypotension. Neither approach was better on the combined incidence of hypotension and hypoxemia.

The 599 peptide has been previously shown to effectively deliver small interfering RNAs (siRNAs) to cancer cells, inducing targeted-oncogene silencing, with a consequent inhibition of tumor growth. Although effective, this study was undertaken to advance the 599 peptide siRNA-carrier design through L/D-amino acid stereochemical modifications. Consequently, 599 was modified to generate eight different peptide variants, incorporating either different stereochemical patterns of L/D-amino acids or a specific D-amino acid substitution. Upon analysis of the variants, it was observed that these modifications could, in some instances, increase/decrease the binding, nuclease/serum stability, and complex release of siRNAs, as well as influence the gene-silencing efficiencies of the complex. These modifications were also found to affect cellular uptake and intracellular localization patterns of siRNA cargo, with one particular variant capable of mediating binding of siRNAs to specific cellular projections, identified as filopodia. Interestingly, this variant also exhibited the most enhanced gene silencing in comparison to the parent 599 peptide, thus suggesting a possible connection between filopodia binding and enhanced gene silencing. Together, these data demonstrate the utility of peptide stereochemistry, as well as the importance of a key D-amino acid modification, in advancing the 599 carrier design for the enhancement of gene silencing in cancer cells., Graphical abstract, In the present study, Jakymiw and colleagues demonstrate the utility of specific L/D-amino acid stereochemical modifications in advancing a peptide siRNA-carrier design for the enhancement of gene silencing in cancer cells, with a possible connection to a more efficient mode of cell entry mediated by filopodia.

We sought data on the validity, reliability, responsiveness, and feasibility of the coefficient of fat absorption (CFA) as a measure of pancreatic enzyme replacement therapy (PERT) efficacy in people with cystic fibrosis (pwCF) and reviewed the literature for alternative measures.We searched PubMed for the Medical Subject Heading cystic fibrosis and the key words cystic fibrosis, fat absorption, CFA, and fecal fat imbalance; historical articles; and citations in bibliographies.The lower the CFA, the greater its variability; thus, it is less variable in healthy individuals who have higher CFA than pwCF. In addition, the test-retest values for CFA are more variable in pwCF than the general population. There is no correlation between CFA and body mass index or PERT dose but CFA is related to gastrointestinal signs and symptoms. Research-quality CFA studies are expensive, time consuming, and odious to pwCF and research staff. Sparse stool tests, breath tests, and blood tests of fat absorption have been studied as potential alternatives to CFA to measure PERT efficacy.Based on the evidence, we conclude that CFA as a measure of the efficacy of PERT is more of a "coal standard" than a gold standard; developing suitable alternatives should be a priority.

The widespread use of complementary products poses a challenge to clinicians in the perioperative period and may increase perioperative risk. Because dietary supplements are regulated differently from traditional pharmaceuticals and guidance is often lacking, the Society for Perioperative Assessment and Quality Improvement convened a group of experts to review available literature and create a set of consensus recommendations for the perioperative management of these supplements. Using a modified Delphi method, the authors developed recommendations for perioperative management of 83 dietary supplements. We have made our recommendations to discontinue or continue a dietary supplement based on the principle that without a demonstrated benefit, or with a demonstrated lack of harm, there is little downside in temporarily discontinuing an herbal supplement before surgery. Discussion with patients in the preoperative visit is a crucial time to educate patients as well as gather vital information. Patients should be specifically asked about use of dietary supplements and cannabinoids, as many will not volunteer this information. The preoperative clinic visit provides the best opportunity to educate patients about the perioperative management of various supplements as this visit is typically scheduled at least 2 weeks before the planned procedure.

BACKGROUND: The poor prognosis of esophageal adenocarcinoma (EAC) has focused efforts on early detection by serial endoscopic surveillance of Barrett’s esophagus (BE). Previously, we reported that receipt of endoscopy before EAC diagnosis was associated with improved survival. AIM: We aimed to refine our previous analysis, assessing surveillance as measured by performance of serial endoscopy before EAC diagnosis and evaluating its association with stage and survival. METHODS: A retrospective cohort study was performed using the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Patients aged ≥ 70 years with EAC diagnosed 1998–2009 were identified. Diagnosis with BE and receipt of ≥ 2 upper endoscopic procedures within 5 years before cancer diagnosis were identified. We compared a reference group not receiving serial endoscopy to 3 patterns based on ≥ 2 endoscopy dates relative to a timepoint 2 years before cancer diagnosis: “remote,” “recent,” and “sustained.” RESULTS: Among 5,532 patients, 28% (n=1,575) had localized stage. Thirteen percent (n=703) received ≥ 2 endoscopic procedures before cancer diagnosis: 224, 298, and 181 in the “recent,” “remote,” and “sustained” groups. Serial endoscopy and prior BE were associated with localized stage (“sustained” group OR 2.95, 95% confidence interval [CI] 2.07, 4.19; prior BE OR 2.68, 95% CI 2.03, 3.56). Serial endoscopy was associated with improved survival even with adjustment for lead time bias (“sustained” group HR 0.45, 95% CI 0.37, 0.55) and length time bias. CONCLUSIONS: Sustained endoscopy was associated with earlier stage and improved survival. These results support the role of sustained surveillance in early detection of EAC.

INTRODUCTION: Oxidation-reduction (redox) reactions, and the redox potential (RP) that must be maintained for proper cell function, lie at the heart of physiologic processes in critical illness. Imbalance in RP reflects systemic oxidative stress, and whole blood RP measures have been shown to correlate with oxygen debt level over time in swine traumatic shock. We hypothesize that RP measures will reflect changing concentrations of metabolites involved in oxidative stress. To test this hypothesis, we compared blood and urine RP with concentrations of multiple metabolites in a swine traumatic shock model to identify meaningful RP-metabolite relationships. METHODS: Seven swine were subjected to traumatic shock. Mixed venous (MV) RP, urine RP, and concurrent MV and urine metabolite concentrations were assessed at baseline, max O2 Debt (80mL/kg), end resuscitation, and 2 hrs post resuscitation. RP was measured at collection via open circuit potential using nanoporous gold electrodes with Ag/AgCl reference and a ParstatMC potentiostat. Metabolite concentrations were measured by quantitative 1H-NMR spectroscopy. MV and urine RP were compared with time-matched metabolites across all swine. LASSO regression with leave-one-out cross validation was used to determine meaningful RP/metabolite relationships. Metabolites had to maintain magnitude and direction of coefficients across 6 or more swine to be considered as having a meaningful relationship. KEGG IDs of these metabolites were uploaded into Metscape for pathway identification and evaluation for physiologic function. RESULTS: Meaningful metabolite relationships (and mean coefficients) with MV RP include: Choline (−6.27), ATP (−4.39), Glycine (5.93), ADP (1.84), Glucose (15.96), Formate (−13.09), Pyruvate (6.18), and Taurine (−7.18). Relationships with urine RP were: cis-Aconitate (4.55)Taurine (7.40), Glycine (−4.88) Creatine (8.16), Betaine (5.11), Urea (6.30), 3-Hydroxyisobutyrate (−6.44), N-Phenylacetylglycine, PAG (−15.48), Hippurate (10.66), and Formate (−5.36). Pathway analysis revealed these metabolites scavenge extracellular peroxide (pyruvate), inhibit ROS and activate cellular antioxidant defense (taurine), act as indicators of antioxidant mobilization against oxidative stress (glycine + PAG), and reflect renal hydroxyl radical trapping (hippurate), among other activity. CONCLUSIONS: Real-time RP measures demonstrate significant relationships with metabolites attributable to metabolic pathways involved in systemic responses to oxidative stress, as well as those active in these processes. These data support RP measures as a feasible, biologically relevant marker of oxidative stress. As a direct measure of redox state, RP may be a useful biomarker and clinical tool in guiding diagnosis and therapy in states of increased oxidative stress, and may offer value as a marker for organ injury in these states as well.

Cerebrovascular autoregulation (CA) is often impaired following traumatic brain injury. Established technologies and metrics used to assess CA are invasive and conducive for measurement, but not for continuous monitoring. We developed a trans-ocular brain impedance (TOBI) method that may provide non-invasive and continuous indices to assess CA. In this study, we monitored impedance metrics such as respiratory-induced impedance amplitude changes (dz) as well as a novel impedance index (DZx), which is a moving Pearson correlation between mean arterial pressure (MAP) and dz. Yorkshire swine were instrumented to continuously record ICP, MAP, and cerebral blood flow (CBF). TOBI was recorded by placement of standard ECG electrodes on closed eyelids and connected to a data acquisition system. MAP, ICP and CBF were manipulated utilizing an intravenous vasopressor challenge. TOBI indices (dz and DZx) were compared to the hemodynamic indicators as well as pressure reactivity index (PRx). During the vasopressor challenge, dz was highly correlated with ICP, CPP, and CBF (r =

BackgroundDespite the significant healthcare impact of acute kidney injury, little is known regarding prevention. Single-center data have implicated hypotension in developing postoperative acute kidney injury. The generalizability of this finding and the interaction between hypotension and baseline patient disease burden remain unknown. The authors sought to determine whether the association between intraoperative hypotension and acute kidney injury varies by preoperative risk.MethodsMajor noncardiac surgical procedures performed on adult patients across eight hospitals between 2008 and 2015 were reviewed. Derivation and validation cohorts were used, and cases were stratified into preoperative risk quartiles based upon comorbidities and surgical procedure. After preoperative risk stratification, associations between intraoperative hypotension and acute kidney injury were analyzed. Hypotension was defined as the lowest mean arterial pressure range achieved for more than 10 min; ranges were defined as absolute (mmHg) or relative (percentage of decrease from baseline).ResultsAmong 138,021 cases reviewed, 12,431 (9.0%) developed postoperative acute kidney injury. Major risk factors included anemia, estimated glomerular filtration rate, surgery type, American Society of Anesthesiologists Physical Status, and expected anesthesia duration. Using such factors and others for risk stratification, patients with low baseline risk demonstrated no associations between intraoperative hypotension and acute kidney injury. Patients with medium risk demonstrated associations between severe-range intraoperative hypotension (mean arterial pressure less than 50 mmHg) and acute kidney injury (adjusted odds ratio, 2.62; 95% CI, 1.65 to 4.16 in validation cohort). In patients with the highest risk, mild hypotension ranges (mean arterial pressure 55 to 59 mmHg) were associated with acute kidney injury (adjusted odds ratio, 1.34; 95% CI, 1.16 to 1.56). Compared with absolute hypotension, relative hypotension demonstrated weak associations with acute kidney injury not replicable in the validation cohort.ConclusionsAdult patients undergoing noncardiac surgery demonstrate varying associations with distinct levels of hypotension when stratified by preoperative risk factors. Specific levels of absolute hypotension, but not relative hypotension, are an important independent risk factor for acute kidney injury.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

We previously reported that the duration of hospitalization was not different between isoflurane and sevoflurane. But more plausible consequences of using soluble volatile anesthetics are delayed emergence from anesthesia and prolonged stays in the postanesthesia care unit (PACU). We therefore compared isoflurane and sevoflurane on emergence time and PACU duration.We reanalyzed data from 1498 adults who participated in a previous alternating intervention trial comparing isoflurane and sevoflurane. Patients, mostly having colorectal surgery, were assigned to either volatile anesthetic in 2-week blocks that alternated for half a year. Emergence time was defined as the time from minimum alveolar concentration fraction reaching 0.3 at the end of the procedure until patients left the operating room. PACU duration was defined from admission to the end of phase 1 recovery. Treatment effect was assessed using Cox proportional hazards regression, adjusted for imbalanced baseline variables.A total of 674 patients were given isoflurane, and 824 sevoflurane. Emergence time was slightly longer for isoflurane with a median (quartiles) of 16 minutes (12-22 minutes) vs 14 minutes (11-19 minutes) for sevoflurane, with an adjusted hazard ratio of 0.81 (97.5% CI, 0.71-0.92; P.001). Duration in the PACU did not differ, with a median (quartiles) of 2.6 hours (2.0-3.6 hours) for isoflurane and 2.6 hours (2.0-3.7 hours) hours for sevoflurane. The adjusted hazard ratio for PACU discharge time was 1.04 (97.5% CI, 0.91-1.18; P = .56).Isoflurane prolonged emergence by only 2 minutes, which is not a clinically important amount, and did not prolong length of stay in the PACU. The more soluble and much less-expensive anesthetic isoflurane thus seems to be a reasonable alternative to sevoflurane.

Polymer materials containing dynamic bonds have many potential applications including adhesives, elastomers, and coatings with long lifetimes. Interpenetrated networks (IPNs) were studied, where on...

Background: Advance care planning allows patients to share their preferences for medical care with the aim of ensuring goal-concordant care in times of serious illness. The morbidity and mortality of the COVID-19 pandemic has increased the importance and public visibility of advance care planning. However, little is known about the frequency and quality of advance care planning documentation during the pandemic. Aim: This study examined the frequency, quality, and predictors of advance care planning documentation among hospitalized medical patients with and without COVID-19. Design: This retrospective cohort analysis used multivariate logistic regression to identify factors associated with advance care planning documentation. Setting/participants: This study included all adult patients tested for COVID-19 and admitted to a tertiary medical center in San Francisco, CA during March 2020. Results: Among 262 patients, 31 (11.8%) tested positive and 231 (88.2%) tested negative for SARS-CoV-2. The rate of advance care planning documentation was 38.7% in patients with COVID-19 and 46.8% in patients without COVID-19 ( p = 0.45). Documentation consistently addressed code status (100% and 94.4% for COVID-positive and COVID-negative, respectively), but less often named a surrogate decision maker, discussed prognosis, or elaborated on other wishes for care. Palliative care consultation was associated with increased advance care planning documentation (OR: 6.93, p = 0.004). Conclusion: This study found low rates of advance care planning documentation for patients both with and without COVID-19 during an evolving global pandemic. Advance care planning documentation was associated with palliative care consultation, highlighting the importance of such consultation to ensure timely, patient-centered advance care planning.