Michael E. DeBakey VA Medical Center

priate starting point for consultation by specialists. Substantial overlap exists among the patients whom these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (HCAP). Pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the HCAP guidelines. However, certain other patients whose conditions are included in the designation of HCAP are better served by management in accordance with CAP guidelines with concern for specific pathogens.

Each year, more than half a million people worldwide receive a diagnosis of hepatocellular carcinoma, and hepatocellular carcinoma related to HCV is the fastest rising cause of U.S. cancer-related deaths. This review summarizes recent advances in prevention, surveillance, diagnosis, and treatment.

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. According to the International Agency for Research on Cancer, liver cancer is the fifth most common cancer in men worldwide (523,000 cases/y, 7.9% of all cancers) and the seventh most common cancer in women (226,000 cases/y, 6.5% of all cancers). Liver cancer has a high mortality rate; the geographic distribution of mortality is similar to that of incidence. Most of the burden of liver cancer is in developing countries, where almost 85% of the cases occur. Hepatocellular carcinoma (HCC) is the most common form of liver cancer; most cases of HCC (approximately 80%) are associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. Variations in the age-, sex-, and race-specific rates of HCC in different geographic regions are likely to be related to differences in the prevalence of hepatitis viruses in the populations, as well as the timing of the spread of the viral infection and the age of individuals at the time of the infection. Most cases of HCC (>80%) occur in sub-Saharan Africa and in Eastern Asia, with typical incidence rates of more than 20 per 100,000 individuals. Southern European countries (such as Spain, Italy, and Greece) tend to have mid-incidence levels (10.0–20.0 per 100,000 individuals), whereas North America, South America, Northern Europe, and Oceania have a low incidence of HCC (<5.0 per 100,000 individuals) (Figure 1). Recent decreases in the incidence of HCC were reported among Chinese populations in Hong Kong, Shanghai, and Singapore; the incidence in Japan also is decreasing. However, cases of HCC are increasing in low-incidence areas such as the United States and Canada. HCC rarely is seen during the first 4 decades of life, except in populations in which HBV infection is hyperendemic. The mean ages of diagnosis with HCC were 55–59 years in China and 63–65 years in Europe and North America. In low-risk populations, the highest incidence of HCC is among individuals aged 75 or older. However, in Qidong, China, where HCC burden is among the world's highest, the age-specific incidence rates among men increases until age 45 years and then plateaus; among women, the incidence rate increases until age 60 years and then plateaus. HCC is predominant among men, with the highest male:female ratios in areas of high incidence (Figure 1). HBV and HCV promote cirrhosis, which is found in 80%–90% of patients with HCC. The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection), region or ethnicity (it is highest in Asians), and stage of cirrhosis (it is highest in individuals with decompensated disease).1Fattovich G. Stroffolini T. Zagni I. et al.Hepatocellular carcinoma in cirrhosis: incidence and risk factors.Gastroenterology. 2004; 127: S35-S50Abstract Full Text Full Text PDF PubMed Scopus (2061) Google Scholar Approximately 5% of the world population (350–400 million people) is chronically infected with HBV; 75% of infected people are Asian,2McMahon B.J. Alberts S.R. Wainwright R.B. et al.Hepatitis B-related sequelae Prospective study in 1400 hepatitis B surface antigen-positive Alaska native carriers.Arch Intern Med. 1990; 150: 1051-1054Crossref PubMed Google Scholar with a lower prevalence (0.3%–1.5%) in Western countries. There is high ecologic correlation between areas of HBV prevalence and HCC incidence and mortality worldwide (Figure 2). Chronic HBV infection accounts for approximately 50% of the total cases and virtually all childhood HCC; it is the dominant risk factor in most areas of Asia and sub-Saharan Africa that have a high incidence of HCC, with the exception of Japan, where the major risk factor for HCC is chronic HCV infection. HB surface antigen (HBsAg) seroprevalence among persons with HCC varies widely: it is 3% in Sweden, 10% in the United States, 10%–15% in Japan, 19% in Italy, 55% in Greece, and 70% in South Korea. The global prevalence of HCV is estimated to be 2% (approximately 180 million people worldwide) and varies considerably among different regions (Figure 2). Phylogenetic studies of HCV diversity described the chronology of the spread of HCV epidemics in Japan, Europe, and the United States; these findings account for the geographic differences in the timing of the burden of HCV-related HCC.3Mizokami M. Orito E. 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Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

BACKGROUND: Many patients report symptomatic relief after undergoing arthroscopy of the knee for osteoarthritis, but it is unclear how the procedure achieves this result. We conducted a randomized, placebo-controlled trial to evaluate the efficacy of arthroscopy for osteoarthritis of the knee. METHODS: A total of 180 patients with osteoarthritis of the knee were randomly assigned to receive arthroscopic débridement, arthroscopic lavage, or placebo surgery. Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope. Patients and assessors of outcome were blinded to the treatment-group assignment. Outcomes were assessed at multiple points over a 24-month period with the use of five self-reported scores--three on scales for pain and two on scales for function--and one objective test of walking and stair climbing. A total of 165 patients completed the trial. RESULTS: At no point did either of the intervention groups report less pain or better function than the placebo group. For example, mean (+/-SD) scores on the Knee-Specific Pain Scale (range, 0 to 100, with higher scores indicating more severe pain) were similar in the placebo, lavage, and débridement groups: 48.9+/-21.9, 54.8+/-19.8, and 51.7+/-22.4, respectively, at one year (P=0.14 for the comparison between placebo and lavage; P=0.51 for the comparison between placebo and débridement) and 51.6+/-23.7, 53.7+/-23.7, and 51.4+/-23.2, respectively, at two years (P=0.64 and P=0.96, respectively). Furthermore, the 95 percent confidence intervals for the differences between the placebo group and the intervention groups exclude any clinically meaningful difference. CONCLUSIONS: In this controlled trial involving patients with osteoarthritis of the knee, the outcomes after arthroscopic lavage or arthroscopic débridement were no better than those after a placebo procedure.

OBJECTIVE: To present results of the Kyoto Global Consensus Meeting, which was convened to develop global consensus on (1) classification of chronic gastritis and duodenitis, (2) clinical distinction of dyspepsia caused by Helicobacter pylori from functional dyspepsia, (3) appropriate diagnostic assessment of gastritis and (4) when, whom and how to treat H. pylori gastritis. DESIGN: Twenty-three clinical questions addressing the above-mentioned four domains were drafted for which expert panels were asked to formulate relevant statements. A Delphi method using an anonymous electronic system was adopted to develop the consensus, the level of which was predefined as ≥80%. Final modifications of clinical questions and consensus were achieved at the face-to-face meeting in Kyoto. RESULTS: All 24 statements for 22 clinical questions after extensive modifications and omission of one clinical question were achieved with a consensus level of >80%. To better organise classification of gastritis and duodenitis based on aetiology, a new classification of gastritis and duodenitis is recommended for the 11th international classification. A new category of H. pylori-associated dyspepsia together with a diagnostic algorithm was proposed. The adoption of grading systems for gastric cancer risk stratification, and modern image-enhancing endoscopy for the diagnosis of gastritis, were recommended. Treatment to eradicate H. pylori infection before preneoplastic changes develop, if feasible, was recommended to minimise the risk of more serious complications of the infection. CONCLUSIONS: A global consensus for gastritis was developed for the first time, which will be the basis for an international classification system and for further research on the subject.

Gastroesophageal reflux disease (GERD) is arguably the most common disease encountered by the gastroenterologist. It is equally likely that the primary care providers will find that complaints related to reflux disease constitute a large proportion of their practice. The following guideline will provide an overview of GERD and its presentation, and recommendations for the approach to diagnosis and management of this common and important disease. The document will review the presentations of any risk factors for GERD, the diagnostic modalities and their recommendation for use and recommendations for medical, surgical and endoscopic management including comparative effectiveness of different treatments. Extraesophageal symptoms and complications will be addressed as will the evaluation and management of "refractory" GERD. The document will conclude with the potential risks and side effects of the main treatments for GERD and their implications for patient management. Each section of the document will present the key recommendations related to the section topic and a subsequent summary of the evidence supporting those recommendations. An overall summary of the key recommendations is presented in Table 1. A search of OVID Medline, Pubmed and ISI Web of Science was conducted for the years from 1960–2011 using the following major search terms and subheadings including "heartburn", "acid regurgitation", "GERD", "lifestyle interventions", "proton pump inhibitor (PPI)", "endoscopic surgery," "extraesophageal symptoms," "Nissen fundoplication," and "GERD complications." We used systematic reviews and meta-analyses for each topic when available followed by a review of clinical trials.Table 1: Summary and strength of recommendationsTable 1: (continued)The GRADE system was used to evaluate the strength of the recommendations and the overall level of evidence (1,2). The level of evidence could range from "high" (implying that further research was unlikely to change the authors' confidence in the estimate of the effect) to "moderate" (further research would be likely to have an impact on the confidence in the estimate of effect) or "low" (further research would be expected to have an important impact on the confidence in the estimate of the effect and would be likely to change the estimate). The strength of a recommendation was graded as "strong" when the desirable effects of an intervention clearly outweigh the undesirable effects and as "conditional" when there is uncertainty about the trade-offs. It is important to be aware that GERD is defined by consensus and as such is a disease comprising symptoms, end-organ effects and complications related to the reflux of gastric contents into the esophagus, oral cavity, and/or the lung. Taking into account the multiple consensus definitions previously published (3,4,5), the authors have used the following working definition to define the disease: GERD should be defined as symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung. GERD can be further classified as the presence of symptoms without erosions on endoscopic examination (non-erosive disease or NERD) or GERD symptoms with erosions present (ERD). SYMPTOMS AND EPIDEMIOLOGY Epidemiologic estimates of the prevalence of GERD are based primarily on the typical symptoms of heartburn and regurgitation. A systematic review found the prevalence of GERD to be 10–20% of the Western world with a lower prevalence in Asia (6). Clinically troublesome heartburn is seen in about 6% of the population (7). Regurgitation was reported in 16% in the systematic review noted above. Chest pain may be a symptom of GERD, even the presenting symptom (2,3). Distinguishing cardiac from non-cardiac chest pain is required before considering GERD as a cause of chest pain. Although the symptom of dysphagia can be associated with uncomplicated GERD, its presence warrants investigation for a potential complication including an underlying motility disorder, stricture, ring, or malignancy (8). Chronic cough, asthma, chronic laryngitis, other airway symptoms and so-called extraesophageal symptoms are discussed in a subsequent section. Atypical symptoms including dyspepsia, epigastric pain, nausea, bloating, and belching may be indicative of GERD but overlap with other conditions. A systematic review found that ∼38% of the general population complained of dyspepsia. Dyspepsia was more frequent in GERD patients than those without. These patients were at risk for a new diagnosis of GERD. Epigastric pain, early satiety, belching and bloating were more likely to respond to a PPI therapy compared with nausea. Overall, these symptoms can be considered to be associated with GERD if they respond to a PPI trial (9). A recent systematic review on the burden of GERD on quality of life (QOL) included 19 studies. Patients with disruptive GERD (daily or >weekly symptoms) had an increase in time off work and decrease in work productivity. Low scores on sleep scales were seen compared with patients with less frequent symptoms. A decrease in physical functioning was also seen (10). Nocturnal GERD has a greater impact on QOL compared with daytime symptoms. Both nocturnal symptoms and sleep disturbances are critical to elucidate when evaluating the GERD patient (11). The balance of evidence suggests that symptom frequency does not change as we age, however, the intensity of symptoms may decrease after the age of 50 (12). Aging increases the prevalence of erosive esophagitis, Los Angeles (LA) grades C and D (13). Barrett's esophagus increases in prevalence after age 50, especially in Caucasian males (14). There are little data addressing the features of GERD in women distinct from men. Patients with erosive esophagitis are more likely to be men, and women are more likely to have NERD. Barrett's esophagus is more frequent in men compared with women (15). The gender ratio for esophageal adenocarcinoma is estimated to be 8:1 male to female (14). There is a definite relationship between GERD and obesity. Several meta-analysis suggest an association between body mass index (BMI), waist circumference, weight gain and the presence of symptoms and complications of GERD including ERD and Barrett's esophagus (16,17). The ProGERD study, likely the largest of its kind (>5,000 patients) used logistic regression analysis to identify several independent risk factors for ERD. The odds for higher degrees of ERD increased as BMI rose (18). It is of greatest concern that there has been a well-documented association between BMI and carcinoma of the esophagus and gastric cardia (19). Establishing the diagnosis of GERDFigure: No Caption available.The diagnosis of GERD is made using some combination of symptom presentation, objective testing with endoscopy, ambulatory reflux monitoring, and response to antisecretory therapy. (Table 2) The symptoms of heartburn and regurgitation are the most reliable for making a presumptive diagnosis based on history alone; however, these are not as sensitive as most believe. A systematic review of seven studies found the sensitivity of heartburn and regurgitation for the presence of erosive esophagitis to be 30–76% and the specificity from 62–96% (20). Empiric PPI therapy (a PPI trial) is a reasonable approach to confirm GERD when it is suspected in patients with typical symptoms. A response to therapy would ideally confirm the diagnosis; however, a well done meta-analysis suggested some limitations of this approach with a sensitivity of 78% and specificity of 54% (21). Therefore, empiric therapy (or a so called PPI trial) has some limitations.Table 2: Diagnostic testing for GERD and utility of testsNon-cardiac chest pain has often been associated with the presence of GERD, and can be the presenting symptom. A meta-analysis found a high probability that non-cardiac chest pain responds to aggressive acid suppression (22). This study supported earlier work suggesting the efficacy and cost effectiveness of a PPI trial (PPI twice daily in variable doses) in patients with chest pain in whom a cardiac cause had been excluded. However, a more recent systematic review suggested that the response of non-cardiac chest pain to a PPI trial was significantly higher than placebo in patients with objective evidence of GERD (ERD on endoscopy and/or abnormal pH monitoring) (23). The response to PPIs compared with placebo was almost non-existent in the absence of objective documentation of GERD. As such, a diagnostic evaluation with endoscopy and pH monitoring should be considered before a PPI trial (24). The presence of heartburn in conjunction with chest pain was not predictive of PPI response of the chest pain component. Dysphagia has historically been an alarm symptom or warning sign and an indication for early endoscopy to rule out a GERD complication. Respiratory symptoms have been associated with GERD, based on retrospective case–control studies. In addition, dental erosions, erosion of dental enamel, sinusitis, chronic laryngitis and voice disturbance have similarly been associated with GERD. These are discussed later in the article. Overall, heartburn and regurgitation remain reliable symptoms of GERD as does non-cardiac chest pain. Other symptoms, while associated with GERD, are not as reliable. The causal relationship between GERD and the so-called atypical and extraesophageal manifestations remains difficult with only a history. Barium radiographs have been historically considered part of the potential diagnostic armamentarium in the patient with esophageal symptoms, including GERD. Although well-performed barium esophagrams with double contrast can detect signs of esophagitis, the overall sensitivity of this test is extremely low (25). The finding of barium reflux above the thoracic inlet with or without provocative maneuvers including the water siphon test does increase the sensitivity of the barium test; however, not sufficiently to be recommended as a diagnostic test without dysphagia (26). The endoscope has long been the primary tool used to evaluate the esophageal mucosa in patients with symptoms suspected due to GERD. Findings of GERD include erosive esophagitis, strictures, and a columnar lined esophagus ultimately confirmed to be Barrett's esophagus. As such, endoscopy has excellent specificity for the diagnosis of GERD especially when erosive esophagitis is seen and the LA classification is used (27). However, the vast majority of patients with heartburn and regurgitation will not have erosions (or Barrett's) limiting upper endoscopy as an initial diagnostic test in patients with suspected GERD (28). Endoscopy allows for biopsy of rings and strictures and screening for Barrett's. Although epidemiologic risk factors for Barrett's esophagus have been well-defined (age over 50, symptoms for>5–10 years, obesity, male sex) the sensitivity and specificity of these symptoms for abnormal endoscopy makes the utility of screening for Barrett's a controversial topic. Recent data indicate that it may be reasonable to perform endoscopy for screening in certain high-risk groups in particular overweight white males over the age of 50 with chronic GERD symptoms (12). The finding of any Barrett's esophagus segment has been associated with pathologic GERD and generally obviates the need for pH testing (29). In a 2009 study, 90% of short-segment BE patients were found to have abnormal pH-impedance testing (30). The addition of esophageal biopsies as an adjunct to an endoscopic examination has been re-emphasized because of the increased prevalence of eosinophilic esophagitis (EoE). Many clinicians routinely biopsy the esophagus in patients with reflux-type symptoms to look for EoE in the setting of an endoscopy that does not reveal erosive changes. Unfortunately, differentiating GERD from EoE using only biopsy is difficult and risks making a diagnosis and instituting treatment without supportive data. Low eosinophil counts in the distal esophagus while suggestive of GERD are not specific. In addition, a high eosinophil count may be seen with GERD and respond to PPIs (PPI responsive eosinophilia) (31). The sensitivity of the other histologic findings; basal cell hyperplasia, elongation of the rete pegs, papillary elongation, and even neutrophils, are of limited clinical usefulness (32,33). There are no studies examining the efficacy of PPIs based on microscopic findings alone. The use of routine biopsy of the esophagus to diagnose GERD cannot be recommended in a patient with heartburn and a normal endoscopy based on current literature. In addition, the practice of obtaining mucosal biopsies from a normal appearing esophagogastric junction has not been demonstrated to be useful in GERD patients (34). Esophageal manometry is of limited value in the primary diagnosis of GERD. Neither a decreased lower esophageal sphincter pressure, nor the presence of a motility abnormality is specific enough to make a diagnosis of GERD. Manometry should be used to aid in placement of transnasal pH-impedance probes and is recommended before consideration of antireflux surgery primarily to rule out achalasia or severe hypomotility (scleroderma-like esophagus), conditions that would be contraindications to Nissen fundoplication, but not to tailor the operation. Ambulatory reflux monitoring (pH or impedance-pH) is the only test that allows for determining the presence of abnormal esophageal acid exposure, reflux frequency, and symptom association with reflux episodes. Performed with either a telemetry capsule (usually 48 h) or transnasal catheter (24 h), pH monitoring has excellent sensitivity (77–100%) and specificity (85–100%) in patients with erosive esophagitis; however, the sensitivity is lower in those with endoscopy-negative reflux symptoms (<71%) when a diagnostic test is more likely to be needed (24). A consensus statement (35) suggested that impedance added to pH monitoring increased the sensitivity of reflux monitoring to close to 90%. Telemetry capsule pH monitoring offers increased patient tolerability and the option to extend the monitoring period to 48 or perhaps to 96 h. The additional monitoring period allows for combining and on and off therapy study in selected situations and offers additional opportunity to correlate symptoms with acid reflux. Catheter-based monitoring allows for the addition of impedance and detection of weakly acidic or non-acid reflux. Optimal use of these two options is certainly debated as is whether to test on or off therapy. As a true diagnostic test (is abnormal acid exposure present) and for evaluation before considering surgery in a patient with NERD an off therapy test is recommended. The use of on and off therapy monitoring in refractory GERD is discussed subsequently. When symptom correlation is required, the decision is more difficult. The two symptom association measures most often used are symptom index (SI) and symptom association probability (SAP). Both have methodological shortcomings that have been reviewed elsewhere (36) and prospective data to validate the ability of these symptom association measures to predict response to treatment is scarce. Both the SI and SAP have been validated when pH monitoring is performed off therapy in a patient with heartburn. A positive test on therapy, coupled with a symptom relationship, theoretically suggests GERD as a cause for symptoms but outcome studies are lacking for any symptom other than heartburn. For patient management, a strongly positive SI or SAP may suggest the need for a therapeutic intervention and a negative result supports the notion that the patient's symptoms are unlikely to be due to reflux. However, these indices should not be used in isolation and other reflux monitoring parameters as well the patient's presentation have to be taken into account. The relationship between H. pylori infection and GERD is controversial. As such, a full discussion is beyond the scope of this article. One issue most often discussed is whether treatment of H. pylori should be altered because of an exacerbation of GERD and if patients on long-term PPIs require screening and subsequent eradication of the bug to prevent the possibility of increasing risk of gastric cancer. A meta-analysis of 12 studies found no increase in GERD (erosive esophagitis) in patients with dyspeptic symptoms who were eradicated compared with those not. This same study found, in subgroup analysis, patients with peptic ulcer disease might experience the new onset of GERD symptoms after H. pylori eradication (37). Concern for the use of long-term PPI therapy in patients with H. pylori infection has been raised because of the potential for development of atrophic gastritis in infected patients on long-term PPI (38). This study prompted a Food and Drug Administration (FDA) review panel that concluded that the evidence was not sufficient to recommend testing of all patients on long-term PPI. The flaws in this study and lack of observational data on negative outcomes lead us to recommend against screening of GERD patients for H. pylori despite the European recommendation in favor of screening (39). GERD is frequent during pregnancy, manifests as heartburn, and may begin in any trimester. One study found onset of 52% in the first trimester, 40% in the second trimester, and 8% in the third trimester (40). Among 607 pregnant women attending an antenatal clinic, 22% experienced heartburn in the first trimester, 39% in the second, and 72% in the third, whereas only 14% of these women reported mild heartburn before their pregnancy (41). Severity also increased throughout pregnancy. Significant predictors of heartburn are increasing gestational age, heartburn before pregnancy, and parity. Maternal age is inversely correlated with heartburn. Race, pre-pregnancy BMI, and weight gain in pregnancy do not correlate with the onset of heartburn. Despite its frequent occurrence during pregnancy, heartburn usually resolves after delivery (42). Pregnancy and amount of weight gain during pregnancy were risk factors for frequent GERD symptoms 1 year post delivery (43). No other GERD symptom has been studied in pregnancy. The diagnosis of GERD during pregnancy should be based on symptoms and treatment symptom-based. Additional diagnostic testing is generally not required for the majority of patients with suspected GERD. In the occasional pregnant patient who does require testing, upper endoscopy is the test of choice, but should be reserved for patients whose symptoms are refractory to medical therapy or who have suspected complications. If possible however, endoscopy should be delayed until after the first trimester. It is uncommon to require ambulatory pH monitoring during pregnancy. Management of GERDFigure: No Caption available.SUMMARY OF THE EVIDENCE Lifestyle interventions are part of therapy for GERD. (Table 3) Counseling is often provided regarding weight loss, head of bed elevation, tobacco and alcohol cessation, avoidance of late-night meals, and cessation of foods that can potentially aggravate reflux symptoms including caffeine, coffee, chocolate, spicy foods, highly acidic foods such as oranges and tomatoes, and foods with high fat content.Table 3: Efficacy of lifestyle interventions for GERDA systematic review (44) evaluated the effect of dietary and other lifestyle modifications on lower esophageal sphincter pressure, esophageal pH, and GERD symptoms. Consumption of tobacco (12 trials), chocolate (2 trials), and carbonated beverages (2 trials) and right lateral decubitus position (3 trials) were shown to lower pressure of the lower esophageal sphincter (LES), whereas consumption of alcohol (16 trials), coffee and caffeine (14 trials), spicy foods (2 trials), citrus (3 trials), and fatty foods trials) had no There was an increase in esophageal acid exposure with tobacco and alcohol consumption in addition to of chocolate and fatty However, tobacco and alcohol cessation trials) were not shown to esophageal pH, or GERD symptoms. In addition, there have been no studies conducted to that have shown clinical in GERD symptoms or complications associated with cessation of coffee, caffeine, chocolate, spicy foods, carbonated fatty foods, or A recent systematic review concluded that there was lack of evidence that consumption of carbonated beverages or GERD gain even in with a normal BMI has been associated with new onset of GERD symptoms studies have demonstrated in GERD symptoms with weight gastric but not has been demonstrated to be in of GERD symptoms A large case–control study based on the demonstrated a 40% in frequent GERD symptoms for women who their BMI by or more compared with of the position has been associated with of esophageal pH and GERD symptoms. have demonstrated in GERD symptoms and esophageal pH with head of bed using or options for patients lifestyle interventions include or PPI therapy. A meta-analysis published in demonstrated that the placebo response in GERD clinical and was lower in patients with erosive esophagitis and PPI compared with with PPI therapy has been associated with and decreased compared with and placebo for patients with erosive esophagitis A meta-analysis demonstrated for all grades of erosive esophagitis using PPI therapy compared with or placebo The overall proportion of or treatment was with PPIs or placebo PPIs a significantly and placebo PPIs provided more heartburn PPIs are associated with a greater of symptom in patients with ERD compared to patients with NERD the symptom For patients with reflux a systematic review demonstrated for PPI therapy compared with and for heartburn the of with over the risk for heartburn primary efficacy in for PPI was confidence for and for In a PPIs were more than and There are seven available PPIs including that can be and are available only by and to in efficacy for symptom between PPIs A meta-analysis published in examining efficacy of PPI therapy for of erosive esophagitis included studies patients) for and there was a increase in the probability of of erosive esophagitis with an risk of and needed to of The by LA of erosive esophagitis were 50, and an 8% increase in the probability of GERD symptom at The clinical of this is of the PPIs with the of and should be before to an has been demonstrated to more nocturnal gastric pH in the first of sleep compared with other PPIs when each is at this effect to any clinical outcomes including symptom further is a delayed PPI in of compared only with demonstrated in esophageal pH in and the of to the any time of the of to in of erosive esophagitis was demonstrated in with in study As it would be expected that of patients with ERD would on PPI therapy and of patients with NERD. of GERD symptoms after a of PPI therapy has been found in of patients and does not in patients PPI or twice The evaluation and management of patients with response are discussed in the refractory GERD section. factors for lack of symptom have included patients with of presence of extraesophageal symptoms, and lack of PPIs are most in pH when taken before a and are generally less when taken at The to this rule to be for the of to have efficacy in pH of and can pH when at is common in practice Although PPI is common in clinical there is limited data to this practice. from trial demonstrated that in GERD patients refractory to patients to therapy daily was as as increasing to twice daily There is no data to PPIs more than in or PPI therapy should be for GERD patients who to have symptoms after PPI is and in patients with complications including erosive esophagitis and Barrett's esophagus. In patients found to have of the patients will off of PPIs over time For patients found to have LA esophagitis, will by In patients found to have any of retrospective studies have suggested a decreased risk for in patients PPI the other studies have demonstrated that patients with NERD and GERD can be with or PPI therapy. In a trial published in of NERD patients to of on were in at compared with of patients on In a systematic review of PPI studies were included in NERD with NERD and mild esophagitis, and studies with The for patients in the were to for patients on PPI therapy and to placebo in patients with but not for patients with ERD. therapy to is option for NERD patients options for GERD patients with response to PPI therapy are The addition of has been recommended for patients with symptoms refractory to PPI. This approach after multiple pH studies demonstrated pH One study suggested potential of pH after a of therapy In of this study and a lack of prospective clinical trial use of a might be most if on as needed in patients with symptoms and patients with objective evidence on pH monitoring of esophageal acid reflux despite PPI therapy with in addition to PPI therapy is option often considered for these has been shown to increase esophageal and gastric data additional of to PPI therapy has not been therapy of with has not been shown to be more compared with or therapy The of has been limited by system side effects including and in of patients in the absence of there is no for in GERD. For the of patients who may from a option is a

BACKGROUND: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. METHODS: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. RESULTS: In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. CONCLUSIONS: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

BACKGROUND: Since the patient's skin is a major source of pathogens that cause surgical-site infection, optimization of preoperative skin antisepsis may decrease postoperative infections. We hypothesized that preoperative skin cleansing with chlorhexidine-alcohol is more protective against infection than is povidone-iodine. METHODS: We randomly assigned adults undergoing clean-contaminated surgery in six hospitals to preoperative skin preparation with either chlorhexidine-alcohol scrub or povidone-iodine scrub and paint. The primary outcome was any surgical-site infection within 30 days after surgery. Secondary outcomes included individual types of surgical-site infections. RESULTS: A total of 849 subjects (409 in the chlorhexidine-alcohol group and 440 in the povidone-iodine group) qualified for the intention-to-treat analysis. The overall rate of surgical-site infection was significantly lower in the chlorhexidine-alcohol group than in the povidone-iodine group (9.5% vs. 16.1%; P=0.004; relative risk, 0.59; 95% confidence interval, 0.41 to 0.85). Chlorhexidine-alcohol was significantly more protective than povidone-iodine against both superficial incisional infections (4.2% vs. 8.6%, P=0.008) and deep incisional infections (1% vs. 3%, P=0.05) but not against organ-space infections (4.4% vs. 4.5%). Similar results were observed in the per-protocol analysis of the 813 patients who remained in the study during the 30-day follow-up period. Adverse events were similar in the two study groups. CONCLUSIONS: Preoperative cleansing of the patient's skin with chlorhexidine-alcohol is superior to cleansing with povidone-iodine for preventing surgical-site infection after clean-contaminated surgery. (ClinicalTrials.gov number, NCT00290290.)

The major barrier to research and development of effective interventions for human noroviruses (HuNoVs) has been the lack of a robust and reproducible in vitro cultivation system. HuNoVs are the leading cause of gastroenteritis worldwide. We report the successful cultivation of multiple HuNoV strains in enterocytes in stem cell-derived, nontransformed human intestinal enteroid monolayer cultures. Bile, a critical factor of the intestinal milieu, is required for strain-dependent HuNoV replication. Lack of appropriate histoblood group antigen expression in intestinal cells restricts virus replication, and infectivity is abrogated by inactivation (e.g., irradiation, heating) and serum neutralization. This culture system recapitulates the human intestinal epithelium, permits human host-pathogen studies of previously noncultivatable pathogens, and allows the assessment of methods to prevent and treat HuNoV infections.

Free radicals derived from oxygen, nitrogen and sulphur molecules in the biological system are highly active to react with other molecules due to their unpaired electrons. These radicals are important part of groups of molecules called reactive oxygen/nitrogen species (ROS/RNS), which are produced during cellular metabolism and functional activities and have important roles in cell signalling, apoptosis, gene expression and ion transportation. However, excessive ROS attack bases in nucleic acids, amino acid side chains in proteins and double bonds in unsaturated fatty acids, and cause oxidative stress, which can damage DNA, RNA, proteins and lipids resulting in an increased risk for cardiovascular disease, cancer, autism and other diseases. Intracellular antioxidant enzymes and intake of dietary antioxidants may help to maintain an adequate antioxidant status in the body. In the past decades, new molecular techniques, cell cultures and animal models have been established to study the effects and mechanisms of antioxidants on ROS. The chemical and molecular approaches have been used to study the mechanism and kinetics of antioxidants and to identify new potent antioxidants. Antioxidants can decrease the oxidative damage directly via reacting with free radicals or indirectly by inhibiting the activity or expression of free radical generating enzymes or enhancing the activity or expression of intracellular antioxidant enzymes. The new chemical and cell-free biological system has been applied in dissecting the molecular action of antioxidants. This review focuses on the research approaches that have been used to study oxidative stress and antioxidants in lipid peroxidation, DNA damage, protein modification as well as enzyme activity, with emphasis on the chemical and cell-free biological system.

The 5-year survival rate in esophageal cancer, although poor, has improved over the past decade. This review discusses the epidemiologic aspects, pathogenesis, prevention, and therapy of esophageal adenocarcinoma and squamous-cell carcinoma, focusing on recent advances.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

BACKGROUND: The association of body mass index and gastroesophageal reflux disease (GERD), including its complications (esophagitis, Barrett esophagus, and esophageal adenocarcinoma), is unclear. PURPOSE: To conduct a systematic review and meta-analysis to estimate the magnitude and determinants of an association between obesity and GERD symptoms, erosive esophagitis, Barrett esophagus, and adenocarcinoma of the esophagus and of the gastric cardia. DATA SOURCES: MEDLINE search between 1966 and October 2004 for published full studies. STUDY SELECTION: Studies that provided risk estimates and met criteria on defining exposure and reporting outcomes and sample size. DATA EXTRACTION: Two investigators independently performed standardized search and data abstraction. Unadjusted and adjusted odds ratios for individual outcomes were obtained or calculated for each study and were pooled by using a random-effects model. DATA SYNTHESIS: Nine studies examined the association of body mass index (BMI) with GERD symptoms. Six of these studies found statistically significant associations. Six of 7 studies found significant associations of BMI with erosive esophagitis, 6 of 7 found significant associations with esophageal adenocarcinoma, and 4 of 6 found significant associations with gastric cardia adenocarcinoma. In data from 8 studies, there was a trend toward a dose-response relationship with an increase in the pooled adjusted odds ratios for GERD symptoms of 1.43 (95% CI, 1.158 to 1.774) for BMI of 25 kg/m2 to 30 kg/m2 and 1.94 (CI, 1.468 to 2.566) for BMI greater than 30 kg/m2. Similarly, the pooled adjusted odds ratios for esophageal adenocarcinoma for BMI of 25 kg/m2 to 30 kg/m2 and BMI greater than 30 kg/m2 were 1.52 (CI, 1.147 to 2.009) and 2.78 (CI, 1.850 to 4.164), respectively. LIMITATIONS: Heterogeneity in the findings was present, although it was mostly in the magnitude of statistically significant positive associations. No studies in this review examined the association between Barrett esophagus and obesity. CONCLUSION: Obesity is associated with a statistically significant increase in the risk for GERD symptoms, erosive esophagitis, and esophageal adenocarcinoma. The risk for these disorders seems to progressively increase with increasing weight.

Perineural invasion (PNI) is the process of neoplastic invasion of nerves and is an under-recognized route of metastatic spread. It is emerging as an important pathologic feature of many malignancies, including those of the pancreas, colon and rectum, prostate, head and neck, biliary tract, and stomach. For many of these malignancies, PNI is a marker of poor outcome and a harbinger of decreased survival. PNI is a distinct pathologic entity that can be observed in the absence of lymphatic or vascular invasion. It can be a source of distant tumor spread well beyond the extent of any local invasion; and, for some tumors, PNI may be the sole route of metastatic spread. Despite increasing recognition of this metastatic process, there has been little progress in the understanding of molecular mechanisms behind PNI and, to date, no targeted treatment modalities aimed at this pathologic entity. The objectives of this review were to lay out a clear definition of PNI to highlight its significance in those malignancies in which it has been studied best. The authors also summarized current theories on the molecular mediators and pathogenesis of PNI and introduced current research models that are leading to advancements in the understanding of this metastatic process.

OBJECTIVE: To examine potential sources of errors at each step of the described inpatient International Classification of Diseases (ICD) coding process. DATA SOURCES/STUDY SETTING: The use of disease codes from the ICD has expanded from classifying morbidity and mortality information for statistical purposes to diverse sets of applications in research, health care policy, and health care finance. By describing a brief history of ICD coding, detailing the process for assigning codes, identifying where errors can be introduced into the process, and reviewing methods for examining code accuracy, we help code users more systematically evaluate code accuracy for their particular applications. STUDY DESIGN/METHODS: We summarize the inpatient ICD diagnostic coding process from patient admission to diagnostic code assignment. We examine potential sources of errors at each step and offer code users a tool for systematically evaluating code accuracy. PRINCIPLE FINDINGS: Main error sources along the "patient trajectory" include amount and quality of information at admission, communication among patients and providers, the clinician's knowledge and experience with the illness, and the clinician's attention to detail. Main error sources along the "paper trail" include variance in the electronic and written records, coder training and experience, facility quality-control efforts, and unintentional and intentional coder errors, such as misspecification, unbundling, and upcoding. CONCLUSIONS: By clearly specifying the code assignment process and heightening their awareness of potential error sources, code users can better evaluate the applicability and limitations of codes for their particular situations. ICD codes can then be used in the most appropriate ways.

Poststroke depression (PSD) has been recognized by psychiatrists for more than 100 years, but controlled systematic studies did not begin until the 1970s. Meta-analyses addressing almost all major clinical issues in the field have emerged because of the relatively small number of patients included in some stroke studies. In order to build large databases, these meta-analyses have merged patients with rigorously assessed mood disorders with major depressive features with patients scoring above arbitrary cutoff points on depression rating scales, thus missing important findings such as cognitive impairment associated with major but not minor depression. Nevertheless, PSD occurs in a significant number of patients and constitutes an important complication of stroke, leading to greater disability as well as increased mortality. The most clinically important advances, however, have been in the treatment and prevention of PSD. Recent meta-analyses of randomized controlled trials for the treatment of PSD have demonstrated the efficacy of antidepressants. Similarly, randomized controlled trials for prevention of PSD have shown that antidepressants significantly decrease the incidence of PSD compared with placebo. Early antidepressant treatment of PSD appears to enhance both physical and cognitive recovery from stroke and might increase survival up to 10 years following stroke. There has also been progress in understanding the pathophysiology of PSD. Inflammatory processes might be associated with the onset of at least some depressive symptoms. In addition, genetic and epigenetic variations, white matter disease, cerebrovascular deregulation, altered neuroplasticity, and changes in glutamate neurotransmission might be relevant etiological factors. Further elucidation of the mechanism of PSD may ultimately lead to specific targeted treatments.