From patterns to patients: Advances in clinical machine learning for cancer diagnosis, prognosis, and treatment.

Machine learning (ML) is increasingly used in clinical oncology to diagnose cancers, predict patient outcomes, and inform treatment planning. Here, we review recent applications of ML across the clinical oncology workflow. We review how these techniques are applied to medical imaging and to molecular data obtained from liquid and solid tumor biopsies for cancer diagnosis, prognosis, and treatment design. We discuss key considerations in developing ML for the distinct challenges posed by imaging and molecular data. Finally, we examine ML models approved for cancer-related patient usage by regulatory agencies and discuss approaches to improve the clinical usefulness of ML.

Leveraging physiology and artificial intelligence to deliver advancements in health care.

Artificial intelligence in health care has experienced remarkable innovation and progress in the last decade. Significant advancements can be attributed to the utilization of artificial intelligence to transform physiology data to advance health care. In this review, we explore how past work has shaped the field and defined future challenges and directions. In particular, we focus on three areas of development. First, we give an overview of artificial intelligence, with special attention to the most relevant artificial intelligence models. We then detail how physiology data have been harnessed by artificial intelligence to advance the main areas of health care: automating existing health care tasks, increasing access to care, and augmenting health care capabilities. Finally, we discuss emerging concerns surrounding the use of individual physiology data and detail an increasingly important consideration for the field, namely the challenges of deploying artificial intelligence models to achieve meaningful clinical impact.

Gut Microbiota Drive Autoimmune Arthritis by Promoting Differentiation and Migration of Peyer's Patch T Follicular Helper Cells.

Gut microbiota profoundly affect gut and systemic diseases, but the mechanism whereby microbiota affect systemic diseases is unclear. It is not known whether specific microbiota regulate T follicular helper (Tfh) cells, whose excessive responses can inflict antibody-mediated autoimmunity. Using the K/BxN autoimmune arthritis model, we demonstrated that Peyer's patch (PP) Tfh cells were essential for gut commensal segmented filamentous bacteria (SFB)-induced systemic arthritis despite the production of auto-antibodies predominantly occurring in systemic lymphoid tissues, not PPs. We determined that SFB, by driving differentiation and egress of PP Tfh cells into systemic sites, boosted systemic Tfh cell and auto-antibody responses that exacerbated arthritis. SFB induced PP Tfh cell differentiation by limiting the access of interleukin 2 to CD4(+) T cells, thereby enhancing Tfh cell master regulator Bcl-6 in a dendritic cell-dependent manner. These findings showed that gut microbiota remotely regulated a systemic disease by driving the induction and egress of gut Tfh cells.

A comprehensive evaluation of hemodynamic energy production and circuit loss using four different ECMO arterial cannulae.

OBJECTIVE: Pulsatile-flow veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has shown encouraging results for microcirculation resuscitation and left ventricle unloading in patients with refractory cardiogenic shock. We aimed to comprehensively assess different V-A ECMO parameters and their contribution to hemodynamic energy production and transfer through the device circuit. METHODS: We used the i-cor® ECMO circuit, which composed of Deltastream DP3 diagonal pump and i-cor® console (Xenios AG), the Hilite 7000 membrane oxygenator (Xenios AG), venous and arterial tubing and a 1 L soft venous pseudo-patient reservoir. Four different arterial cannulae (Biomedicus 15 and 17 Fr, Maquet 15 and 17 Fr) were used. For each cannula, 192 different pulsatile modes were investigated by adjusting flow rate, systole/diastole ratio, pulsatile amplitudes and frequency, yielding 784 unique conditions. A dSpace data acquisition system was used to collect flow and pressure data. RESULTS: Increasing flow rates and pulsatile amplitudes were associated with significantly higher hemodynamic energy production (both p < 0.001), while no significant associations were seen while adjusting systole-to-diastole ratio (p = 0.73) or pulsing frequency (p = 0.99). Arterial cannula represents the highest resistance to hemodynamic energy transfer with 32%-59% of total hemodynamic energy generated being lost within, depending on pulsatile flow settings used. CONCLUSIONS: Herein, we presented the first study to compare hemodynamic energy production with all pulsatile ECLS pump settings and their combinations and widely used yet previously unexamined four different arterial ECMO cannula. Only increased flow rate and amplitude increase hemodynamic energy production as single factors, whilst other factors are relevant when combined.

Minimally Invasive Versus Open Radical Antegrade Modular Pancreatosplenectomy: A Meta-Analysis.

BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) was introduced to improve the tangential resection margin rates and N1 node clearance following resection of malignancies of the pancreatic body and tail. Owing to its technical complexity, minimally invasive RAMPS (MI-RAMPS) has only been reported by a few centers worldwide. We performed this meta-analysis to compare both short- and long-term outcomes between open RAMPS (O-RAMPS) and minimally invasive RAMPS (MI-RAMPS). METHODS: A systematic search of the electronic databases PubMed, Medline (via PubMed), Cochrane Register of Controlled Trials (CENTRAL), EMBASE, Scopus and Web of Science was performed to identify eligible studies published in the English language regardless of study design. The outcomes of interest were operation time, estimated blood loss, transfusion rates, overall complications, Grade B/C post-operative pancreatic fistula (POPF) rates, post-pancreatectomy hemorrhage (PPH), delayed gastric emptying (DGE), length of stay (LOS), R0 resection rates, lymph node (LN) yield and overall survival (OS). RESULTS: Five non-randomized studies comprising of a total 229 patients (89 MI-RAMPS, 140 O-RAMPS) were included for analysis. Intra-operative blood loss was observed to be significantly reduced in MI-RAMPS as compared to O-RAMPS (MD -256.16, P < 0.001), while LN yield was higher in O-RAMPS as compared to MI-RAMPS (MD -2.73, P = 0.02). There were no statistically significant differences observed for the other perioperative, oncologic and survival outcomes. CONCLUSIONS: This meta-analysis provides early evidence to suggest that MI-RAMPS may produce comparable short- and long-term outcomes to O-RAMPS, when undertaken by appropriately skilled surgeons in well-selected patients. Further large-scale prospective studies are required to corroborate these findings.

A mock circulation loop to evaluate differential hypoxemia during peripheral venoarterial extracorporeal membrane oxygenation.

INTRODUCTION: Peripheral veno-arterial extracorporeal membrane oxygenation (VA ECMO) creates a retrograde flow along the aorta competing with the left ventricle (LV) in the so-called 'mixing zone' (MZ). Detecting it is essential to understand which of the LV or the ECMO flow perfuses the upper body - particularly the brain and the coronary arteries - in case of differential hypoxemia (DH). METHODS: We described a mock circulation loop (MCL) that enabled experimental research on DH. We recreated the three clinical situations relevant to clinicians: where the brain is either totally perfused by the ECMO or the LV or both. In a second step, we used this model to investigate two scenarios to diagnose DH: (i) pulse pressure and (ii) thermodilution via injection of cold saline in the ECMO circuit. RESULTS: The presented MCL was able to reproduce the three relevant mixing zones within the aortic arch, thus allowing to study DH. Pulse pressure was unable to detect location of the MZ. However, the thermodilution method was able to detect whether the brain was totally perfused by the ECMO or not. CONCLUSION: We validated an in-vitro differential hypoxemia model of cardiogenic shock supported by VA ECMO. This MCL could be used as an alternative to animal studies for research scenarios.

Broad-Spectrum Antiviral Entry Inhibition by Interfacially Active Peptides.

Numerous peptides inhibit the entry of enveloped viruses into cells. Some of these peptides have been shown to inhibit multiple unrelated viruses. We have suggested that such broad-spectrum antiviral peptides share a property called interfacial activity; they are somewhat hydrophobic and amphipathic, with a propensity to interact with the interfacial zones of lipid bilayer membranes. In this study, we further tested the hypothesis that such interfacial activity is a correlate of broad-spectrum antiviral activity. In this study, several families of peptides, selected for the ability to partition into and disrupt membrane integrity but with no known antiviral activity, were tested for the ability to inhibit multiple diverse enveloped viruses. These include Lassa pseudovirus, influenza virus, dengue virus type 2, herpes simplex virus 1, and nonenveloped human adenovirus 5. Various families of interfacially active peptides caused potent inhibition of all enveloped viruses tested at low and submicromolar concentrations, well below the range in which they are toxic to mammalian cells. These membrane-active peptides block uptake and fusion with the host cell by rapidly and directly interacting with virions, destabilizing the viral envelope, and driving virus aggregation and/or intervirion envelope fusion. We speculate that the molecular characteristics shared by these peptides can be exploited to enable the design, optimization, or molecular evolution of novel broad-spectrum antiviral therapeutics.IMPORTANCE New classes of antiviral drugs are needed to treat the ever-changing viral disease landscape. Current antiviral drugs treat only a small number of viral diseases, leaving many patients with established or emerging infections to be treated solely with supportive care. Recent antiviral peptide research has produced numerous membrane-interacting peptides that inhibit diverse enveloped viruses in vitro and in vivo Peptide therapeutics are becoming more common, with over 60 FDA-approved peptides for clinical use. Included in this class of therapeutics is enfuvirtide, a 36-residue peptide drug that inhibits HIV entry/fusion. Due to their broad-spectrum mechanism of action and enormous potential sequence diversity, peptides that inhibit virus entry could potentially fulfill the need for new antiviral therapeutics; however, a better understanding of their mechanism is needed for the optimization or evolution of sequence design to combat the wide landscape of viral disease.

Laparoscopic versus open resection of hepatocellular carcinoma in patients with cirrhosis: meta-analysis.

BACKGROUND: The exact role of laparoscopic liver resection (LLR) in patients with hepatocellular carcinoma (HCC) and underlying liver cirrhosis (LC) is not well defined. In this meta-analysis, both long- and short-term outcomes following LLR versus open liver resection (OLR) were analysed. METHODS: PubMed, EMBASE, Scopus and Web of Science databases were searched systematically for randomised controlled trials (RCTs) and propensity-score matched (PSM) studies reporting outcomes of LLR versus OLR of HCC in patients with cirrhosis. Primary outcome was overall survival (OS). This was analysed using one-stage (individual participant data meta-analysis) and two-stage (aggregate data meta-analysis) approaches. Secondary outcomes were operation duration, blood loss, blood transfusion, Pringle manoeuvre utilization, overall and major complications, length of hospital stay (LOHS), 90-day mortality and R0 resection rates. RESULTS: Eleven studies comprising 1618 patients (690 LLR versus 928 OLR) were included for analysis. In the one-stage meta-analysis, an approximately 18.7 per cent lower hazard rate (HR) of death in the LLR group (random effects: HR 0.81, 95 per cent confidence interval [C.I.] 0.68 to 0.96; P = 0.018) was observed. Two-stage meta-analysis resulted in a pooled HR of 0.84 (95 per cent C.I. 0.74 to 0.96; P = 0.01) in the overall LLR cohort. This indicated a 16-26 per cent reduction in the HR of death for patients with HCC and cirrhosis who underwent LLR. For secondary outcomes, LLR was associated with less blood loss (mean difference [MD] -99 ml, 95 per cent C.I. -182 to -16 ml), reduced overall complications (odds ratio 0.49, 95 per cent C.I. 0.37 to 0.66) and major complications (odds ratio 0.45, 95 per cent C.I. 0.26 to 0.79), and shorter LOHS (MD -3.22 days, 95 per cent C.I. -4.38 to -2.06 days). CONCLUSION: Laparoscopic resection of HCC in patients with cirrhosis is associated with improved survival and perioperative outcomes.

An overview of patients with haemophilia A in China: Epidemiology, disease severity and treatment strategies.

INTRODUCTION: Haemophilia A (HA) is a rare X chromosome-linked bleeding disorder resulting in missing or defective clotting factor VIII (FVIII) and causes large disease burden. AIM: As a member of World Federation of Hemophilia, China seeks to understand the current epidemiology, disease profile and treatment landscape of patients with HA through the Hemophilia Treatment Center Collaboration Network of China (HTCCNC). METHODS: The HTCCNC enabled data collection on patients with HA from 166 member hospitals (2007-2019) across China. The distribution of patients across 31 divisions was summarized using a heat map. Patient demographics, disease severity and clinical and treatment information were summarized using descriptive statistics. RESULTS: HTCCNC identified 17,779 patients with HA during 2007-2019. Patients were predominantly male (99.99%), and 28.3% had a known family history of haemophilia. Among patients with lab-measured disease severity (N = 13,116), 6,519 had severe HA (49.7%), 4,788 had moderate HA (36.5%), and 1,809 had mild HA (13.8%). Among patients with information on the delays, delays in diagnosis and in treatment initiation were observed in 1,437 (28.8%) and 1,750 (39.2%) patients, respectively. On average, those patients had an 8.4 years gap between the first bleed and HA diagnosis and a delay of 8.6 years from the first bleed to treatment initiation. Additionally, 44.33% of patients relied solely on episodic treatments, and 16.2% received any prophylaxis treatments. CONCLUSIONS: Using data from the largest haemophilia registry in China, this study indicated that delayed diagnosis and treatment, together with low utilization of prophylaxis, are key challenges for patients with HA.

Inhibition of fatty acid synthase with FT-4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non-alcoholic fatty liver disease: Results from two early-phase randomized trials.

AIMS: To assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT-4101, a potent, selective, orally bioavailable, small-molecule by (a) evaluating the dose-response of single FT-4101 doses (3, 6 and 9 mg) on hepatic de novo lipogenesis (DNL) in healthy participants (Study 1) and (b) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks of FT-4101 dosing in patients with non-alcoholic fatty liver disease (NAFLD; Study 2). MATERIALS AND METHODS: In Study 1, three sequential cohorts of healthy men (n = 10/cohort) were randomized to receive a single dose of FT-4101 (n = 5/cohort) or placebo (n = 5/cohort) followed by crossover dosing after 7 days. Hepatic DNL was assessed during fructose stimulation from 13 C-acetate incorporation. In Study 2, men and women with NAFLD (n = 14) randomly received 12 weeks of intermittent once-daily dosing (four cycles of 2 weeks on-treatment, followed by 1 week off-treatment) of 3 mg FT-4101 (n = 9) or placebo (n = 5). Steady-state DNL based on deuterated water labelling, hepatic steatosis using magnetic resonance imaging-proton density fat fraction and sebum lipids and circulating biomarkers were assessed. RESULTS: Single and repeat dosing of FT-4101 were safe and well tolerated. Single FT-4101 doses inhibited hepatic DNL dose-dependently. Twelve weeks of 3 mg FT-4101 treatment improved hepatic steatosis and inhibited hepatic DNL. Decreases in sebum sapienate content with FT-4101 at week 11 were not significant compared to placebo and rebounded at week 12. Biomarkers of liver function, glucose and lipid metabolism were unchanged. CONCLUSIONS: Inhibition of FASN with 3 mg FT-4101 safely reduces hepatic DNL and steatosis in NAFLD patients.

Hemophilia Gene Therapy Value Assessment: Methodological Challenges and Recommendations.

Gene therapy for hemophilia is designed to produce health gains for patients over many years. Rewarding that value creation on the basis of a one-time treatment implies a large upfront cost. This cost can only be justified by long-term health benefits and being cost-effective compared with conventional treatments. Yet, uncertainties about the long-term benefits make it challenging to assess clinical and economic value of gene therapies at launch. We identify and discuss key methodological challenges in assessing the value of gene therapy for hemophilia, including the immaturity of evidence on the durability of benefits, lack of definition and valuation of cure for chronic diseases, absence of randomized controlled trials, limitations of traditional quality of life measures in hemophilia, approach for qualifying cost-savings compared with current treatments, and choice of perspective. The Institute for Clinical and Economic Review has developed a framework for assessing single or short-term therapies (ICER-SST) and has applied it in hemophilia. After reviewing this framework and its application, we recommend the following when assessing the value of hemophilia gene therapies: (1) leveraging expert clinical opinion to justify assumptions on the durability of benefits; (2) using external synthetic controls and lead-in, self-controlled trials to assess comparative effectiveness; (3) addressing limitations of traditional quality of life measures through the use of modified utility collection approaches; (4) adjusting cost offsets from gene therapies with caution; (5) considering outcome-based contracting to address uncertainties about prices and long-term outcomes; and (6) presenting societal and healthcare system perspectives in parallel.

Mechanistic Landscape of Membrane-Permeabilizing Peptides.

Membrane permeabilizing peptides (MPPs) are as ubiquitous as the lipid bilayer membranes they act upon. Produced by all forms of life, most membrane permeabilizing peptides are used offensively or defensively against the membranes of other organisms. Just as nature has found many uses for them, translational scientists have worked for decades to design or optimize membrane permeabilizing peptides for applications in the laboratory and in the clinic ranging from antibacterial and antiviral therapy and prophylaxis to anticancer therapeutics and drug delivery. Here, we review the field of membrane permeabilizing peptides. We discuss the diversity of their sources and structures, the systems and methods used to measure their activities, and the behaviors that are observed. We discuss the fact that "mechanism" is not a discrete or a static entity for an MPP but rather the result of a heterogeneous and dynamic ensemble of structural states that vary in response to many different experimental conditions. This has led to an almost complete lack of discrete three-dimensional active structures among the thousands of known MPPs and a lack of useful or predictive sequence-structure-function relationship rules. Ultimately, we discuss how it may be more useful to think of membrane permeabilizing peptides mechanisms as broad regions of a mechanistic landscape rather than discrete molecular processes.

Real-world analysis of haemophilia patients in China: A single centre's experience.

INTRODUCTION: The management of haemophilia is critical to minimize the risk of disability and reduce the burden on China's healthcare system. AIM: This study was based on a single centre in China and was conducted to understand the evolution of real-world haemophilia care over the past 15 years. METHODS: We retrospectively analysed clinical characteristics, diagnosis, treatment and medical expenditures of 428 patients with haemophilia from January 2004 to December 2018 from the Institute of Hematology & Blood Diseases Hospital in Tianjin, China. RESULTS: The delayed diagnosis time significantly decreased from 13.3 ± 5.1 years before 2004 to 0.4 ± 0.4 year in 2014-2018 (P < .05). Among children and adults receiving prophylactic treatment, the annual factor consumption increased from 2004-2008 (168.8 IU/kg in children and 120.7 IU/kg in adults) to 2009-2013 (389.2 IU/kg in children and 316.2 IU/kg in adults) and 2014-2018 (1328.0 IU/kg in children and 878.8 IU/kg in adults, P < .001). The annual medical insurance expenditure for haemophilia had increased steadily over the past 10 years. The number of patients tested regularly for inhibitors increased from 2004 (1.9% [2/105]) to 2018 (21.5% [59/275]). The seroprevalence of hepatitis C virus (HCV) was 33.8% during the years examined, while the incidence rates of HCV among patients significantly decreased (7.3% in 2008 to 0.4% in 2018). CONCLUSION: Significant improvements in the management of haemophilia were observed from 2004 to 2018. These results highlight the joint effort of the reimbursement policy and drug regulatory management paving the way for a better future for patients with haemophilia in China.

An advanced mock circulation loop for in vitro cardiovascular device evaluation.

Controlled and repeatable in vitro evaluation of cardiovascular devices using a mock circulation loop (MCL) is essential prior to in vivo or clinical trials. MCLs often consist of only a systemic circulation with no autoregulatory responses and limited validation. This study aimed to develop, and validate against human data, an advanced MCL with systemic, pulmonary, cerebral, and coronary circulations with autoregulatory responses. The biventricular MCL was constructed with pneumatically controlled hydraulic circulations with Starling responsive ventricles and autoregulatory cerebral and coronary circulations. Hemodynamic repeatability was assessed and complemented by validation using impedance cardiography data from 50 healthy humans. The MCL successfully simulated patient scenarios including rest, exercise, and left heart failure with and without cardiovascular device support. End-systolic pressure-volume relationships for respective healthy and heart failure conditions had slopes of 1.27 and 0.54 mm Hg mL-1 (left ventricle), and 0.18 and 0.10 mm Hg mL-1 (right ventricle), aligning with the literature. Coronary and cerebral autoregulation showed a strong correlation (R2 : .99) between theoretical and experimentally derived circuit flow. MCL repeatability was demonstrated with correlation coefficients being statistically significant (P < .05) for all simulated conditions while MCL hemodynamics aligned well with human data. This advanced MCL is a valuable tool for inexpensive and controlled evaluation of cardiovascular devices.

A Starling-like total work controller for rotary blood pumps: An in vitro evaluation.

Due to improved durability and survival rates, rotary blood pumps (RBPs) are the preferred left ventricular assist device when compared to volume displacement pumps. However, when operated at constant speed, RBPs lack a volume balancing mechanism which may result in left ventricular suction and suboptimal ventricular unloading. Starling-like controllers have previously been developed to balance circulatory volumes; however, they do not consider ventricular workload as a feedback and may have limited sensitivity to adjust RBP workload when ventricular function deteriorates or improves. To address this, we aimed to develop a Starling-like total work controller (SL-TWC) that matched the energy output of a healthy heart by adjusting RBP hydraulic work based on measured left ventricular stroke work and ventricular preload. In a mock circulatory loop, the SL-TWC was evaluated using a HeartWare HVAD in a range of simulated patient conditions. These conditions included changes in systemic hypertension and hypotension, pulmonary hypertension, blood circulatory volume, exercise, and improvement and deterioration of ventricular function by increasing and decreasing ventricular contractility. The SL-TWC was compared to constant speed control where RBP speed was set to restore cardiac output to 5.0 L/min at rest. Left ventricular suction occurred with constant speed control during pulmonary hypertension but was prevented with the SL-TWC. During simulated exercise, the SL-TWC demonstrated reduced LVSW (0.51 J) and greater RBP flow (9.2 L/min) compared to constant speed control (LVSW: 0.74 J and RBP flow: 6.4 L/min). In instances of increased ventricular contractility, the SL-TWC reduced RBP hydraulic work while maintaining cardiac output similar to the rest condition. In comparison, constant speed overworked and increased cardiac output. The SL-TWC balanced circulatory volumes by mimicking the Starling mechanism, while also considering changes in ventricular workload. Compared to constant speed control, the SL-TWC may reduce complications associated with volume imbalances, adapt to changes in ventricular function and improve patient quality of life.

Autonomous sweat extraction and analysis applied to cystic fibrosis and glucose monitoring using a fully integrated wearable platform.

Perspiration-based wearable biosensors facilitate continuous monitoring of individuals' health states with real-time and molecular-level insight. The inherent inaccessibility of sweat in sedentary individuals in large volume (≥10 µL) for on-demand and in situ analysis has limited our ability to capitalize on this noninvasive and rich source of information. A wearable and miniaturized iontophoresis interface is an excellent solution to overcome this barrier. The iontophoresis process involves delivery of stimulating agonists to the sweat glands with the aid of an electrical current. The challenge remains in devising an iontophoresis interface that can extract sufficient amount of sweat for robust sensing, without electrode corrosion and burning/causing discomfort in subjects. Here, we overcame this challenge through realizing an electrochemically enhanced iontophoresis interface, integrated in a wearable sweat analysis platform. This interface can be programmed to induce sweat with various secretion profiles for real-time analysis, a capability which can be exploited to advance our knowledge of the sweat gland physiology and the secretion process. To demonstrate the clinical value of our platform, human subject studies were performed in the context of the cystic fibrosis diagnosis and preliminary investigation of the blood/sweat glucose correlation. With our platform, we detected the elevated sweat electrolyte content of cystic fibrosis patients compared with that of healthy control subjects. Furthermore, our results indicate that oral glucose consumption in the fasting state is followed by increased glucose levels in both sweat and blood. Our solution opens the possibility for a broad range of noninvasive diagnostic and general population health monitoring applications.

Dialysis Catheter-related Bloodstream Infections in Patients Receiving Hemodialysis on an Emergency-only Basis: A Retrospective Cohort Analysis.

BACKGROUND: An estimated 6500 undocumented immigrants with end-stage renal disease (ESRD) live in the United States. Those living in states that do not provide undocumented immigrants scheduled hemodialysis receive intermittent hemodialysis only when life-threatening conditions arise. Little is known about catheter-related bloodstream infections (CRBSIs) in this population. METHODS: We conducted a retrospective cohort study of emergency-only hemodialysis patients in the Harris Health System in Houston, Texas, between January 2012 and December 2015. We assessed CRBSI risk factors including demographics, comorbidities, and duration and frequency of hemodialysis. We investigated the microbiologic etiology of these infections, rates of recurrent CRBSI, and associated morbidity and mortality. RESULTS: The cohort included 329 patients; 90% were Hispanic, 60% had diabetes, and the average age was 51 years. A total of 101 CRBSIs occurred, with a rate of 0.84 infections per 1000 catheter-days. Cirrhosis and duration of hemodialysis during the study period were associated with increased risk of CRBSI. Seventeen CRBSIs were recurrent; infection with gram-positive bacteria predicted recurrence. Adherence to catheter-related infection guidelines was improved by infectious diseases consultation and associated with fewer recurrent infections. CRBSI was associated with prolonged hospitalization (mean, 15 days), composite complication rate of 8%, and a 4% mortality rate. CONCLUSIONS: Patients receiving emergency-only hemodialysis via tunneled catheters have a high CRBSI rate compared with infection rates previously reported in patients receiving scheduled maintenance hemodialysis. Increased CRSBI risk likely contributes to the increased morbidity and mortality seen in ESRD patients receiving emergency-only hemodialysis.

Gastroesophageal and Laryngopharyngeal Reflux Associated With Laryngeal Malignancy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Gastric reflux may lead to chronic mucosal inflammation and contribute to development of laryngeal malignancies, although there is controversy over this association. We performed a systematic review and meta-analysis to assess this relationship and determine the risk of laryngeal malignancy in patients with reflux disease. METHODS: We performed a systematic review and meta-analysis, searching MEDLINE, EMBASE, and Web of Science databases from 1900 through April 9, 2018, for observational studies of adults reporting associations between gastroesophageal reflux disease (GERD) and/or laryngopharyngeal reflux and the risk of having or developing laryngeal malignancies. An itemized assessment of the risk of bias was conducted for each study that met inclusion criteria. The meta-analysis was performed using the Mantel-Haenszel method with random effects to account for heterogeneity. We performed subgroup analyses to determine the effect of reflux type, study design, diagnostic method, and confounding variables on the overall risk. RESULTS: Of the 957 studies that were identified during systematic review, 18 case-control studies met the criteria for analysis. Our meta-analysis showed that reflux disease significantly increased the risk of laryngeal malignancy (odds ratio, 2.47; 95% CI, 1.90-3.21; P < .00001; I2 = 94%). This association remained when controlling for patient smoking and drinking (odds ratio, 2.07; 95% CI, 1.26-3.41). There was no statistically significant difference in risk of laryngeal malignancies between patients with GERD vs laryngopharyngeal reflux (P = .44). CONCLUSIONS: In a systematic review and meta-analysis, we found a significant association between reflux disease and the presence of laryngeal malignancy. Prospective studies should be performed to examine this relationship.

Two-dimensional electronic vibrational spectroscopy and ultrafast excitonic and vibronic photosynthetic energy transfer.

Two-dimensional electronic-vibrational (2DEV) spectroscopy is a new coherent spectroscopic technique, which shows considerable promise for unravelling complex molecular dynamics. In this Discussion we describe an application to the energy transfer pathway in the major light harvesting protein, LHCII, providing new data on the center line slopes (CLS) of the spectral peaks. The CLS provides information that appears unique to the 2DEV method. We then outline a general approach to calculating 2DEV spectra which is valid for strongly and weakly coupled molecular systems. We conclude with some prospects for the future development of 2DEV spectroscopy and its theoretical analysis.

Two-dimensional electronic-vibrational spectroscopic study of conical intersection dynamics: an experimental and electronic structure study.

The relaxation from the lowest singlet excited state of the triphenylmethane dyes, crystal violet and malachite green, is studied via two-dimensional electronic-vibrational (2DEV) spectroscopy. After excitation of the dyes at their respective absorption maxima, the ensuing excited state dynamics are tracked by monitoring the C[double bond, length as m-dash]C aromatic stretch. With the aid of electronic structure calculations, the observed transitions in the 2DEV spectra are assigned to specific geometries and a detailed story of the evolution of the nuclear wavepacket as it diffuses on the excited state potential energy surface (PES) and ultimately passes through the conical intersection is developed. Notably, it is revealed that the relaxation of the lowest singlet excited state involves intramolecular charge transfer while the nuclear wavepacket is on the excited state PES. Finally, through analyzing the center line slopes of the measured peaks, we show how both solvent motions and changes in the molecular dipole moment affect the correlation between electronic and vibrational degrees of freedom. This work clearly demonstrates the usefulness of 2DEV spectroscopy in following the motion of nuclear wavepackets after photoexcitation and in studying the interactions between the molecular dipole moment and surrounding solvent environment.