Prince of Wales Hospital

To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided.

The city of Wuhan in China is the focus of global attention due to an outbreak of a febrile respiratory illness due to a coronavirus 2019-nCoV. In December 2019, there was an outbreak of pneumonia of unknown cause in Wuhan, Hubei province in China, with an epidemiological link to the Huanan Seafood Wholesale Market where there was also sale of live animals. Notification of the WHO on 31 Dec 2019 by the Chinese Health Authorities has prompted health authorities in Hong Kong, Macau, and Taiwan to step up border surveillance, and generated concern and fears that it could mark the emergence of a novel and serious threat to public health (WHO, 2020a; Parr, 2020).

INTRODUCTION Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (1). Sepsis and septic shock are major healthcare problems, impacting millions of people around the world each year and killing between one in three and one in six of those it affects (2–4). Early identification and appropriate management in the initial hours after the development of sepsis improve outcomes. The recommendations in this document are intended to provide guidance for the clinician caring for adult patients with sepsis or septic shock in the hospital setting. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when presented with a unique patient’s clinical variables. These guidelines are intended to reflect best practice (Table 1). TABLE 1. - Table of Current Recommendations and Changes From Previous 2016 Recommendations Recommendations 2021 Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong , moderate-quality evidence (for screening) Changed from Best practice statement “We recommend that hospitals and hospital systems have a performance improvement program for sepsis including sepsis screening for acutely ill, high-risk patients.” Strong , very low-quality evidence (for standard operating procedures) 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single-screening tool for sepsis or septic shock. Strong , moderate-quality evidence NEW 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak , low quality of evidence INITIAL RESUSCITATION 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice statement 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. Weak, low quality of evidence DOWNGRADE from Strong , low quality of evidence “We recommend that in the initial resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hr” 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation, over physical examination, or static parameters alone. Weak , very low quality of evidence 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak , low quality of evidence 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak , low quality of evidence NEW MEAN ARTERIAL PRESSURE 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong , moderate-quality evidence ADMISSION TO INTENSIVE CARE 10. For adults with sepsis or septic shock who require we suggest the patients to the within Weak , low quality of evidence For adults with suspected sepsis or septic shock we recommend and for and an of is or Best practice statement For adults with septic shock or a for sepsis, we recommend within hr of Strong , low quality of evidence from “We recommend that of should be as as after and within one for septic shock and sepsis Strong , very low quality of evidence , quality of evidence For adults with sepsis shock, we recommend of the of of Best practice statement For adults with sepsis shock, we suggest a of and for infection the of within 3 hr from the time when sepsis first Weak , very low quality of evidence NEW from “We recommend that of IV should be as as after and within hr for septic shock and sepsis , quality of evidence For adults with a low of infection and shock, we suggest to the Weak , very low quality of evidence NEW from “We recommend that of IV should be as as after and within hr for septic shock and sepsis , quality of evidence For adults with suspected sepsis or septic shock, we suggest against using clinical to when to as compared to clinical alone. Weak , very low quality of evidence For adults with sepsis or septic shock at of we recommend using with over using Best practice statement NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock at low of we suggest against using with as compared with using Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock and for we suggest using with for treatment over one Weak , very low quality of evidence For adults with sepsis or septic shock and low for we suggest against using for as compared to one Weak , very low quality of evidence For adults with sepsis or septic shock, we suggest against using the and the are Weak , very low quality of evidence For adults with sepsis or septic shock at of we suggest using over Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock at low of we suggest against of Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence We on the of For adults with sepsis or septic shock, we suggest using of for an initial over Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend of on and Best practice statement For adults with sepsis or septic shock, we recommend or a of infection that and as as and Best practice statement For adults with sepsis or septic shock, we recommend of that are a of sepsis or septic shock after other Best practice statement For adults with sepsis or septic shock, we suggest for of over using of for Weak , very low quality of evidence For adults with an initial of sepsis or septic shock and we suggest using over of Weak , very low quality of evidence For adults with an initial of sepsis or septic shock and of is we suggest using clinical to when to over clinical alone. Weak , low quality of evidence For adults with sepsis or septic shock, we recommend using as fluid for resuscitation. Strong , moderate-quality evidence For adults with sepsis or septic shock, we suggest using of for resuscitation. Weak , low quality of evidence from , low quality of “We suggest using or for fluid resuscitation of patients with sepsis or septic For adults with sepsis or septic shock, we suggest using in patients who of Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend against using for resuscitation. Strong , evidence For adults with sepsis and septic shock, we suggest against using for resuscitation. Weak , moderate-quality evidence from , low quality of evidence “We suggest using over when patients with sepsis or septic For adults with septic shock, we recommend using as the over other Strong evidence evidence quality of evidence quality of evidence low-quality evidence For adults with septic shock on with mean arterial pressure we suggest of the of Weak , quality evidence For adults with septic shock and mean arterial pressure and we suggest Weak , low quality of evidence For adults with septic shock, we suggest against using Weak , low quality of evidence For adults with septic shock and dysfunction with hypoperfusion and arterial blood we suggest to or using alone. Weak , low quality of evidence For adults with septic shock and dysfunction with hypoperfusion and arterial blood we suggest against using Weak , low quality of evidence NEW For adults with septic shock, we suggest of arterial blood pressure over as as and are Weak , very low quality of evidence For adults with septic shock, we suggest to mean arterial pressure a is Weak , very low quality of evidence NEW is evidence to a on the of fluid in the first hr of resuscitation in patients with sepsis and septic shock who have of hypoperfusion and after the initial resuscitation. NEW “We suggest using or for fluid resuscitation of patients with sepsis or septic Weak , low quality of evidence “We suggest using over when patients with sepsis or septic Weak , low quality of evidence is evidence to a on the of in adults with sepsis-induced For adults with sepsis-induced we suggest the of over Weak , low quality of evidence NEW is evidence to a on the of in to for adults with sepsis-induced For adults with sepsis-induced we recommend using a low over a Strong , evidence For adults with sepsis-induced we recommend using an for of 30 over higher Strong , moderate-quality evidence For adults with to sepsis-induced we suggest using higher over Weak , moderate-quality evidence For adults with sepsis-induced we suggest using low as compared with Weak , low quality of evidence For adults with sepsis-induced we suggest using Weak , moderate-quality evidence using we recommend against using Strong , moderate-quality evidence For adults with sepsis-induced we recommend using for hr Strong , moderate-quality evidence For adults with sepsis induced we suggest using over Weak , moderate-quality evidence For adults with sepsis-induced we suggest using when in with the in to Weak , low quality of evidence NEW For adults with septic shock and an for we suggest using IV Weak , moderate-quality evidence from Weak , low quality of evidence “We suggest against using IV to septic shock patients fluid resuscitation and are to for this is not we suggest IV at a of For adults with sepsis or septic shock we suggest against using Weak , low quality of evidence NEW from “We the of blood is evidence to a on the of other blood For adults with sepsis or septic shock we recommend using a Strong , moderate-quality evidence For adults with sepsis or septic shock we suggest against using IV Weak , low quality of evidence For adults with sepsis or septic shock, and who have for we suggest using Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend using a to Strong , moderate-quality evidence For adults with sepsis or septic shock, we recommend using low over for Strong , moderate-quality evidence For adults with sepsis or septic shock, we suggest against using in to over alone. Weak , low quality of evidence adults with sepsis or septic shock and we suggest using or Weak , low quality of evidence adults with sepsis or septic shock and with for we suggest against using Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend at a of Strong , moderate-quality evidence For adults with sepsis or septic shock we suggest against using IV Weak , low quality of evidence NEW For adults with septic shock and we suggest against using to improve or to Weak , low quality of evidence For adults with septic shock and and or we suggest using Weak , low quality of evidence For adult patients with sepsis or septic shock who be we suggest of Weak , very low quality of evidence CARE For adults with sepsis or septic shock, we recommend of and with patients and over Best practice statement For adults with sepsis or septic shock, we suggest of over hr or Weak , low quality of evidence For adults with sepsis or septic shock, is evidence to a on to of For adults with sepsis or septic shock, we recommend that the of on clinician be the treatment when to and and Best practice statement For adults with sepsis or septic shock, we suggest against for patients over on clinician Weak , low quality of evidence For adult of sepsis or septic shock and we suggest to over Weak , very low quality of evidence For adults with sepsis or septic shock, we suggest using a of at of over Weak , very low quality of evidence For adults with sepsis or septic shock, is evidence to a on the of tool over For adults with sepsis or septic shock and we recommend screening for and and and to these Best practice statement For adults with sepsis or septic shock and we suggest and sepsis and to hospital and in the setting. Weak , very low quality of evidence For adults with sepsis or septic shock and we recommend the clinical provide the to in in and hospital to are and Best practice statement For adults with sepsis and septic shock and we suggest using a compared with to the Weak , very low quality of evidence For adults with sepsis and septic shock, we recommend at and hospital Best practice statement For adult of sepsis and septic shock and we recommend including the sepsis and and after sepsis in the and hospital Best practice statement For adults with sepsis or septic shock who we recommend hospital with to and and Best practice statement For adults with sepsis or septic shock and is evidence to a on compared with For adults with sepsis or septic shock, is evidence to a for or against For adult of sepsis or septic shock, we recommend and for and after hospital Best practice statement For adult of sepsis or septic shock, we suggest to a program Weak , very low quality of evidence For adult of sepsis or septic shock for or an of we suggest to a Weak , very low quality of evidence are to in the be at for Sepsis and - Recommendation 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong quality of evidence for Strong very low-quality evidence for standard operating Sepsis performance improvement of sepsis of sepsis and for a of on the of performance improvement that these with to sepsis with a in in patients with sepsis and septic shock The of performance improvement not to be as as the of a program that sepsis screening and Sepsis screening are to identification of sepsis and of or of the health is in of these with having the of with in of clinical and are for sepsis as response of or Early or Early improve performance of screening and in a of patients from for hospital sepsis the the operating and higher for the for screening as MEWS and target patients in as or of three not a of screening is in and of sepsis screening are an of sepsis for operating procedures are a of that a response to clinical Sepsis standard operating as Early have to a standard with of the sepsis and the between of sepsis and of sepsis to hospitals in the in a and after of sepsis with a from other this time in hospitals with higher with the sepsis a of in higher with standard operating procedures compared with it in one - Recommendation 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a screening tool for sepsis or septic shock. Strong moderate-quality The qSOFA three to and in patients with or suspected a a and a blood pressure mm of these are the is qSOFA to the recommendations of the on the of Sepsis qSOFA as a of in patients with or suspected to as a screening tool that time have the of the qSOFA as a screening tool for sepsis The have as to have that qSOFA is having of for identification of infection induced organ dysfunction qSOFA are screening for sepsis and the clinician to the of the that of patients a qSOFA or these patients for of have when against the Early and the Early the of a qSOFA should the clinician to the of sepsis in given the of the the a against as a screening - Recommendation 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak low-quality The of lactate with in patients with suspected infection and sepsis is is as of the sepsis for those patients with sepsis and an elevated lactate is of the of septic shock that lactate be to for the of sepsis adult patients with suspected not have the of lactate in this The lactate an elevated from of the from with from and from the three are and an between the of lactate at and the are the of an elevated or lactate or the of a of sepsis in patients with suspected lactate is to or the on not be in we a the of serum lactate as an to the of sepsis in patients with suspected not - Recommendations 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hours of resuscitation. Weak low-quality 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation over physical or static parameters alone. Weak very low-quality parameters response to a or a fluid using pressure or 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak low-quality resuscitation, serum lactate should be the clinical and other of elevated lactate. 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak low-quality fluid resuscitation is for the of sepsis-induced hypoperfusion in sepsis and septic shock. 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Previous of these guidelines have using lactate as a target of resuscitation in the of sepsis and septic shock, on to and of in serum lactate in with or in The that serum lactate are not in patients with septic shock, these that decrease lactate lactate should be the clinical and other of elevated lactate. with sepsis lactate not be in is not measures of organ be to the and of of the and capillary refill time have and to be of The a resuscitation a resuscitation at or lactate by hours in the first hours of septic shock the organ dysfunction as by in the and in the lactate this not the of a on using resuscitation and is and this should be by and to or fluid are of the or to the should management - Recommendation 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong moderate-quality MAP is a of mean in is the major of and MAP in blood and the of perfusion. as the and have the to blood a to be mm are with organ with MAP Previous guidelines a MAP of 65 mm Hg for initial resuscitation. The on a in septic shock patients who given to target a MAP of mm a target of mm Hg in a a in with higher MAP patients with higher MAP with with a higher of of this that the MAP in the of on this that higher MAP not improve in septic shock to and MAP target compared a mm with a that and MAP by the in patients 65 and with septic shock The in this a mean MAP of mm compared with mm Hg in the to in the by of and in in the and the of with higher MAP and the of patients with MAP of mm the a MAP of 65 mm Hg in the initial resuscitation of patients with septic shock who require to - Recommendation 10. For adults with sepsis or septic shock who require we suggest the patients to the within Weak low-quality The of patients on of in an appropriate the septic patients are in the and hospital of patients from are with sepsis and and and hospital of on the time for to the from and an of an in of for each of to of patients in the a higher hospital for the higher to time hr and compared with the to time for of an to time hr with hospital in patients with higher of with sepsis not patients to when hours hospital the a hospital higher and higher of and of patients in hospitals in the that to to higher and on of patients to an in outcomes. is evidence of and are best in an are of patients with sepsis to an not be in in and be this and appropriate treatment should not be of of - Recommendation For adults with suspected sepsis or septic shock we recommend and for and an of is or Best practice of these we the of a for to it is to in a a best practice we that appropriate should be in patients with suspected sepsis and septic shock it in in the of not in this as as The and of sepsis are and other is to sepsis, the cannot have a of sepsis in a with organ a or of patients with sepsis to have Best practice is to the to other are or a patient’s clinical after hospital or the of a of this be in when it is to or major is a that to on the that the is each as in and of the that by or in each in of or that the for a in the or a We not or evidence this are to a an that not from is or this is not of the should the of patients and patients that is not to - Recommendations For adults with septic shock or a for sepsis, we recommend within one of Strong low quality of evidence very low quality of evidence For adults with sepsis shock, we recommend of the of of Best practice and clinical examination, for and of and treatment for that this should be within 3 hours of that a be as to the of an of the patient’s and the of sepsis is to be For adults with sepsis shock, we suggest a of and for infection the of within 3 hours from the time when sepsis first Weak very low quality of For adults with a low of infection and shock, we suggest to the Weak very low quality of Early of appropriate is one of the to in patients with sepsis to patients with sepsis or septic shock should be as an The to provide as as be against the with to patients infection These a of as or and sepsis is as sepsis in and that first to be sepsis to be the of infection and of for each with suspected sepsis should the and of The with in patients with septic shock, have a between time to and in patients with septic shock in patients septic shock a of patients at each of time from to of with of for patients for patients not on a of patients at each of time from to of with of for patients with sepsis at least one of or or organ and for patients with septic to a for sepsis and a for septic shock in a of patients in each in time from to of with of and of in patients with in patients not an between and should be that the and at of to the of with or other patients with sepsis shock, the between time to and within the first hours from is have one to a in between and the other in a in time to suggest that after hours from hospital sepsis We suggest in patients with sepsis shock as as sepsis to be the and 3 hours after sepsis first suspected for sepsis at that given the of with septic shock and the of and the a to and within one in patients with septic shock. for patients with sepsis, we recommend be 1). For patients with sepsis shock, we recommend a of and of be to within 3 should be or should be to the Recommendations on of from suggest that of in patients with sepsis and septic shock is and and of a of in The and time for by and the of and of on is to recommendations to the of in patients with sepsis and septic shock in are in with the recommendations to - Recommendation For adults with suspected sepsis or septic shock, we suggest against using clinical to when to as compared to clinical alone. Weak very low quality of is in in response to in with clinical the of and of a of 30 a of and of for sepsis in patients We evidence from three that compared for of the three in to of to or of to and not in of the and on the with of the and the quality of evidence very guidelines for the management of recommend of for patients with of and in including the a against using to guide in to clinical - Recommendations For adults with sepsis or septic shock at of we recommend using with over using Best practice For adults with sepsis or septic shock at low of we suggest against using with as compared with using Weak low quality of The on to an against in an treatment for sepsis and septic shock the that the patient’s infection is caused by the of with treatment for in a with and the of with treatment in a for of patients and be to The of by from in to in and by for of infection or IV of or of hospital and of on the of including in on patients with the of in patients with of hours are with in not in patients with or sepsis, including against with higher patients The with are by an between of and in patients with or to for in a with be in a be from including the of to for are and on and clinical for are - Recommendations For adults with sepsis or septic shock and for we suggest using with for treatment over one Weak very low quality of For adults with sepsis or septic shock and low for we suggest against using for compared with one Weak very low quality of For adults with sepsis or septic shock, we suggest against using the and the are Weak very low quality of the of in of the world and between in and the initial of is to the at least one that is against the the and are the of on the of for and the of the and are is for patients with in a with of in or other between in adult patients with sepsis or septic shock when from the in the of of and in a low with the from the Recommendations the of one for treatment over one are given clinical including of and the of the of sepsis is to the appropriate For this we from recommendations in patients with sepsis or septic shock recommend the of on of to guide this infection or with within the of within the to a within the and within the the and are is not for patients with with and quality of evidence very and the of with the of for treatment. have an in in patients at for we suggest using for treatment to the of in patients with a low for we suggest using a for as are of using and the a of including infection and development of of is in patients at for with septic shock. - Recommendations For adults with sepsis or septic shock at of we suggest using over Weak low quality of For adults with sepsis or septic shock at low of we suggest against of Weak low quality of Sepsis and septic shock to are in and are with that of appropriate

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

OBJECTIVE: to examine the clinical evidence reporting the prevalence of sarcopenia and the effect of nutrition and exercise interventions from studies using the consensus definition of sarcopenia proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). METHODS: PubMed and Dialog databases were searched (January 2000-October 2013) using pre-defined search terms. Prevalence studies and intervention studies investigating muscle mass plus strength or function outcome measures using the EWGSOP definition of sarcopenia, in well-defined populations of adults aged ≥50 years were selected. RESULTS: prevalence of sarcopenia was, with regional and age-related variations, 1-29% in community-dwelling populations, 14-33% in long-term care populations and 10% in the only acute hospital-care population examined. Moderate quality evidence suggests that exercise interventions improve muscle strength and physical performance. The results of nutrition interventions are equivocal due to the low number of studies and heterogeneous study design. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not shown consistent benefits on muscle mass and function. CONCLUSION: prevalence of sarcopenia is substantial in most geriatric settings. Well-designed, standardised studies evaluating exercise or nutrition interventions are needed before treatment guidelines can be developed. Physicians should screen for sarcopenia in both community and geriatric settings, with diagnosis based on muscle mass and function. Supervised resistance exercise is recommended for individuals with sarcopenia. EAA (with leucine) and HMB may improve muscle outcomes.

BACKGROUND AND METHODS: In preliminary trials, lamivudine, an oral nucleoside analogue, has shown promise for the treatment of chronic hepatitis B. We conducted a one-year, double-blind trial of lamivudine in 358 Chinese patients with chronic hepatitis B. The patients were randomly assigned to receive 25 mg of lamivudine (142 patients), 100 mg of lamivudine (143), or placebo (73) orally once daily. The patients underwent liver biopsies before entering the study and after completing the assigned treatment regimen. The primary end point was a reduction of at least two points in the Knodell necroinflammatory score. RESULTS: Hepatic necroinflammatory activity improved by two points or more in 56 percent of the patients receiving 100 mg of lamivudine, 49 percent of those receiving 25 mg of lamivudine, and 25 percent of those receiving placebo (P<0.001 and P=0.001, respectively, for the comparisons of lamivudine treatment with placebo). Necroinflammatory activity worsened in 7 percent of the patients receiving 100 mg of lamivudine, 8 percent of those receiving 25 mg, and 26 percent of those receiving placebo. The 100-mg dose of lamivudine was associated with a reduced progression of fibrosis (P=0.01 for the comparison with placebo) and with the highest rate of hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg, development of antibody to HBeAg, and undetectable HBV DNA) (16 percent), the greatest suppression of HBV DNA (98 percent reduction at week 52 as compared with the base-line value), and the highest rate of sustained normalization of alanine aminotransferase levels (72 percent). Ninety-six percent of the patients completed the study. The incidence of adverse events was similar in all groups, and there were few serious events. CONCLUSIONS: In a one-year study, lamivudine was associated with substantial histologic improvement in many patients with chronic hepatitis B. A daily dose of 100 mg was more effective than a daily dose of 25 mg.

Today, the need for time-effective and cost-effective nucleic acid detection methods is still growing in fields such as human genotyping and pathogen detection. Using synthetic biomolecular components, many methods have been developed for fast nucleic acid detection 1 , 2 , 3 ; however, they may not be able to satisfy specificity, sensitivity, speed, cost and simplicity at the same time. Recently, a very promising CRISPR-based diagnostic (CRISPR-Dx) (namely SHERLOCK) was established, which was based on the collateral effect of an RNA-guided and RNA-targeting CRISPR effector, Cas13a 4 . SHERLOCK is of high sensitivity and specificity, and is very convenient in detection of target RNA. However, to detect DNA sequences, in vitro transcription of DNA to RNA must be conducted prior to the SHERLOCK test, which could be inconvenient.

Importance: A study published in 2000 showed that more than one-third of adults with epilepsy have inadequate control of seizures with antiepileptic drugs (AEDs). This study evaluates overall treatment outcomes in light of the introduction of more than 1 dozen new AEDs in the past 2 decades. Objective: To assess long-term treatment outcome in patients with newly diagnosed and treated epilepsy. Design, Setting, and Participants: This longitudinal observational cohort study was conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. A total of 1795 individuals who were newly treated for epilepsy with AEDs between July 1, 1982, and October 31, 2012, were included in this analysis. All patients were followed up for a minimum of 2 years (until October 31, 2014) or until death, whichever came sooner. Data analysis was completed between March 2015 and May 2016. Exposures: Treatment with antiepileptic drugs for patients newly diagnosed with epilepsy. Main Outcomes and Measures: Seizure control was assessed at the end of the study period. Probability of achieving 1-year seizure freedom was estimated for each AED regimen prescribed. Multivariable models assessed the associations between risk factors and AED treatment outcome after adjustments were made for demographic and clinical characteristics. Results: Of the 1795 included patients, 964 (53.7%) were male; the median age was 33 years (range, 9-93 years). At the end of the study period, 1144 patients (63.7%) had been seizure free for the previous year or longer. Among those achieving 1-year seizure freedom, 993 (86.8%) were taking monotherapy and 1028 (89.9%) had achieved seizure control with the first or second AED regimens. Of the total patient pool, 906 (50.5%) remained seizure free for 1 year or longer with the initial AED. If this AED failed, the second and third regimens provided an additional 11.6% and 4.4% likelihoods of seizure freedom, respectively. Only 2.12% of patients attained optimal seizure control with subsequent AEDs. Epilepsy that was not successfully controlled with the first AED had 1.73 times greater odds of not responding to treatment for each subsequent medication regimen (odds ratio, 1.73; 95% CI, 1.56-1.91; P < .001). Conclusions and Relevance: Despite the availability of many new AEDs with differing mechanisms of action, overall outcomes in newly diagnosed epilepsy have not improved. Most patients who attain control do so with the first or second AED. The probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen tried. More than one-third of patients experience epilepsy that remains uncontrolled.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

In Brief Objective: To compare the results of percutaneous local ablative therapy (PLAT) with surgical resection in the treatment of solitary and small hepatocellular carcinoma (HCC). Summary Background Data: PLAT is effective in small HCC. Whether it is as effective as surgical resection in the long-term survivals remains unknown. Methods: We conducted a prospective randomized trial on 180 patients with a solitary HCC ≦5 cm to receive either PLAT or surgical resection. The patients were regularly followed up after treatment with physical examination, blood, and radiologic tests. Results: Of the 90 patients who were randomized to PLAT, only 71 received PLAT because 19 withdrew their consent. Of the 90 patients who were randomized to surgical resection, a single Couinaud liver segment resection was carried out in 69 patients, 2 segments in 16 patients, and 3 or more segments in 3 patients. Ethanol injection was given during open surgery in 2 patients. Only 1 patient died after surgical resection within the same hospital admission. Posttreatment complications were more often and severe after surgery than PLAT. The 1-, 2-, 3-, and 4-year overall survival rates after PLAT and surgery were 95.8%, 82.1%, 71.4%, 67.9% and 93.3%, 82.3%, 73.4%, 64.0%, respectively. The corresponding disease-free survival rates were 85.9%, 69.3%, 64.1%, 46.4% and 86.6%, 76.8%, 69%, 51.6%, respectively. Statistically, there was no difference between these 2 treatments. Conclusion: PLAT was as effective as surgical resection in the treatment of solitary and small HCC. PLAT had the advantage over surgical resection in being less invasive. A prospective randomized trial on 180 patients with a solitary hepatocellular carcinoma ≦ 5 cm showed there was no significant difference in the long-term overall and disease-free survivals between treatment with percutaneous local ablative therapy or partial hepatectomy. Percutaneous local ablative therapy has the advantage over surgery in being less invasive.

Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease caused by a novel coronavirus, but its immunopathological mechanisms have not yet been fully elucidated. We investigated changes in plasma T helper (Th) cell cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with SARS. Cytokine profile of SARS patients showed marked elevation of Th1 cytokine interferon (IFN)-gamma, inflammatory cytokines interleukin (IL)-1, IL-6 and IL-12 for at least 2 weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumour necrosis factor (TNF)-alpha, anti-inflammatory cytokine IL-10, Th1 cytokine IL-2 and Th2 cytokine IL-4. The chemokine profile demonstrated significant elevation of neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-gamma-inducible protein-10 (IP-10). Corticosteroid reduced significantly IL-8, MCP-1 and IP-10 concentrations from 5 to 8 days after treatment (all P < 0.001). Together, the elevation of Th1 cytokine IFN-gamma, inflammatory cytokines IL-1, IL-6 and IL-12 and chemokines IL-8, MCP-1 and IP-10 confirmed the activation of Th1 cell-mediated immunity and hyperinnate inflammatory response in SARS through the accumulation of monocytes/macrophages and neutrophils.

Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease caused by a novel single-stranded, positive-sense RNA betacoronavirus (MERS-CoV). Dromedary camels, hosts for MERS-CoV, are implicated in direct or indirect transmission to human beings, although the exact mode of transmission is unknown. The virus was first isolated from a patient who died from a severe respiratory illness in June, 2012, in Jeddah, Saudi Arabia. As of May 31, 2015, 1180 laboratory-confirmed cases (483 deaths; 40% mortality) have been reported to WHO. Both community-acquired and hospital-acquired cases have been reported with little human-to-human transmission reported in the community. Although most cases of MERS have occurred in Saudi Arabia and the United Arab Emirates, cases have been reported in Europe, the USA, and Asia in people who travelled from the Middle East or their contacts. Clinical features of MERS range from asymptomatic or mild disease to acute respiratory distress syndrome and multiorgan failure resulting in death, especially in individuals with underlying comorbidities. No specific drug treatment exists for MERS and infection prevention and control measures are crucial to prevent spread in health-care facilities. MERS-CoV continues to be an endemic, low-level public health threat. However, the virus could mutate to have increased interhuman transmissibility, increasing its pandemic potential.

PURPOSE: We updated the terminology in the field of pediatric lower urinary tract function. MATERIALS AND METHODS: Discussions were held of the board of the International Children's Continence Society and an extensive reviewing process was done involving all members of the International Children's Continence Society as well as other experts in the field. RESULTS AND CONCLUSIONS: New definitions and a standardized terminology are provided, taking into account changes in the adult sphere and new research results.

Pre‐eclampsia (PE) is a multisystem disorder that typically affects 2%–5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Globally, 76 000 women and 500 000 babies die each year from this disorder. Furthermore, women in low‐resource countries are at a higher risk of developing PE compared with those in high‐resource countries. Although a complete understanding of the pathogenesis of PE remains unclear, the current theory suggests a two‐stage process. The first stage is caused by shallow invasion of the trophoblast, resulting in inadequate remodeling of the spiral arteries. This is presumed to lead to the second stage, which involves the maternal response to endothelial dysfunction and imbalance between angiogenic and antiangiogenic factors, resulting in the clinical features of the disorder. Accurate prediction and uniform prevention continue to elude us. The quest to effectively predict PE in the first trimester of pregnancy is fueled by the desire to identify women who are at high risk of developing PE, so that necessary measures can be initiated early enough to improve placentation and thus prevent or at least reduce the frequency of its occurrence. Furthermore, identification of an “at risk” group will allow tailored prenatal surveillance to anticipate and recognize the onset of the clinical syndrome and manage it promptly. PE has been previously defined as the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently, the definition of PE has been broadened. Now the internationally agreed definition of PE is the one proposed by the International Society for the Study of Hypertension in Pregnancy (ISSHP). According to the ISSHP, PE is defined as systolic blood pressure at ≥140 mm Hg and/or diastolic blood pressure at ≥90 mm Hg on at least two occasions measured 4 hours apart in previously normotensive women and is accompanied by one or more of the following new‐onset conditions at or after 20 weeks of gestation: 1.Proteinuria (i.e. ≥30 mg/mol protein:creatinine ratio; ≥300 mg/24 hour; or ≥2 + dipstick); 2.Evidence of other maternal organ dysfunction, including: acute kidney injury (creatinine ≥90 μmol/L; 1 mg/dL); liver involvement (elevated transaminases, e.g. alanine aminotransferase or aspartate aminotransferase >40 IU/L) with or without right upper quadrant or epigastric abdominal pain; neurological complications (e.g. eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, and persistent visual scotomata); or hematological complications (thrombocytopenia–platelet count <150 000/μL, disseminated intravascular coagulation, hemolysis); or 3.Uteroplacental dysfunction (such as fetal growth restriction, abnormal umbilical artery Doppler waveform analysis, or stillbirth). It is well established that a number of maternal risk factors are associated with the development of PE: advanced maternal age; nulliparity; previous history of PE; short and long interpregnancy interval; use of assisted reproductive technologies; family history of PE; obesity; Afro‐Caribbean and South Asian racial origin; co‐morbid medical conditions including hyperglycemia in pregnancy; pre‐existing chronic hypertension; renal disease; and autoimmune diseases, such as systemic lupus erythematosus and antiphospholipid syndrome. These risk factors have been described by various professional organizations for the identification of women at risk of PE; however, this approach to screening is inadequate for effective prediction of PE. PE can be subclassified into: 1.Early‐onset PE (with delivery at <34+0 weeks of gestation); 2.Preterm PE (with delivery at <37+0 weeks of gestation); 3.Late‐onset PE (with delivery at ≥34+0 weeks of gestation); 4.Term PE (with delivery at ≥37+0 weeks of gestation). These subclassifications are not mutually exclusive. Early‐onset PE is associated with a much higher risk of short‐ and long‐term maternal and perinatal morbidity and mortality. Obstetricians managing women with preterm PE are faced with the challenge of balancing the need to achieve fetal maturation in utero with the risks to the mother and fetus of continuing the pregnancy longer. These risks include progression to eclampsia, development of placental abruption and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. On the other hand, preterm delivery is associated with higher infant mortality rates and increased morbidity resulting from small for gestational age (SGA), thrombocytopenia, bronchopulmonary dysplasia, cerebral palsy, and an increased risk of various chronic diseases in adult life, particularly type 2 diabetes, cardiovascular disease, and obesity. Women who have experienced PE may also face additional health problems in later life, as the condition is associated with an increased risk of death from future cardiovascular disease, hypertension, stroke, renal impairment, metabolic syndrome, and diabetes. The life expectancy of women who developed preterm PE is reduced on average by 10 years. There is also significant impact on the infants in the long term, such as increased risks of insulin resistance, diabetes mellitus, coronary artery disease, and hypertension in infants born to pre‐eclamptic women. The International Federation of Gynecology and Obstetrics (FIGO) brought together international experts to discuss and evaluate current knowledge on PE and develop a document to frame the issues and suggest key actions to address the health burden posed by PE. FIGO's objectives, as outlined in this document, are: (1) To raise awareness of the links between PE and poor maternal and perinatal outcomes, as well as to the future health risks to mother and offspring, and demand a clearly defined global health agenda to tackle this issue; and (2) To create a consensus document that provides guidance for the first‐trimester screening and prevention of preterm PE, and to disseminate and encourage its use. Based on high‐quality evidence, the document outlines current global standards for the first‐trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of pre‐eclampsia in singleton pregnancy.1 It provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings. Suggestions are provided for a variety of different regional and resource settings based on their financial, human, and infrastructure resources, as well as for research priorities to bridge the current knowledge and evidence gap. To deal with the issue of PE, FIGO recommends the following: Public health focus: There should be greater international attention given to PE and to the links between maternal health and noncommunicable diseases (NCDs) on the Sustainable Developmental Goals agenda. Public health measures to increase awareness, access, affordability, and acceptance of preconception counselling, and prenatal and postnatal services for women of reproductive age should be prioritized. Greater efforts are required to raise awareness of the benefits of early prenatal visits targeted at reproductive‐aged women, particularly in low‐resource countries. Universal screening: All pregnant women should be screened for preterm PE during early pregnancy by the first‐trimester combined test with maternal risk factors and biomarkers as a one‐step procedure. The risk calculator is available free of charge at https://fetalmedicine.org/research/assess/preeclampsia. FIGO encourages all countries and its member associations to adopt and promote strategies to ensure this. The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI). Where it is not possible to measure PLGF and/or UTPI, the baseline screening test should be a combination of maternal risk factors with MAP, and not maternal risk factors alone. If maternal serum pregnancy‐associated plasma protein A (PAPP‐A) is measured for routine first‐trimester screening for fetal aneuploidies, the result can be included for PE risk assessment. Variations to the full combined test would lead to a reduction in the performance screening. A woman is considered high risk when the risk is 1 in 100 or more based on the first‐trimester combined test with maternal risk factors, MAP, PLGF, and UTPI. Contingent screening: Where resources are limited, routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of PLGF and UTPI for a subgroup of the population (selected on the basis of the risk derived from screening by maternal factors and MAP) can be considered. Prophylactic measures: Following first‐trimester screening for preterm PE, women identified at high risk should receive aspirin prophylaxis commencing at 11–14+6 weeks of gestation at a dose of ~150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed. Low‐dose aspirin should not be prescribed to all pregnant women. In women with low calcium intake (<800 mg/d), either calcium replacement (≤1 g elemental calcium/d) or calcium supplementation (1.5–2 g elemental calcium/d) may reduce the burden of both early‐ and late‐onset PE.

We present an analysis of the first 10 weeks of the severe acute respiratory syndrome (SARS) epidemic in Hong Kong. The epidemic to date has been characterized by two large clusters-initiated by two separate "super-spread" events (SSEs)-and by ongoing community transmission. By fitting a stochastic model to data on 1512 cases, including these clusters, we show that the etiological agent of SARS is moderately transmissible. Excluding SSEs, we estimate that 2.7 secondary infections were generated per case on average at the start of the epidemic, with a substantial contribution from hospital transmission. Transmission rates fell during the epidemic, primarily as a result of reductions in population contact rates and improved hospital infection control, but also because of more rapid hospital attendance by symptomatic individuals. As a result, the epidemic is now in decline, although continued vigilance is necessary for this to be maintained. Restrictions on longer range population movement are shown to be a potentially useful additional control measure in some contexts. We estimate that most currently infected persons are now hospitalized, which highlights the importance of control of nosocomial transmission.

OBJECTIVE: MicroRNAs (miRNAs) have been shown to offer great potential in the diagnosis of cancer. We investigated whether plasma miRNAs could discriminate between patients with and without colorectal cancer (CRC). METHODS: This study was divided into three phases: (1) marker discovery using real-time PCR-based miRNA profiling on plasma, corresponding cancerous and adjacent non-cancerous colonic tissues of five patients with CRC, along with plasma from five healthy individuals as controls; (2) marker selection and validation by real-time quantitative RT-PCR on a small set of plasma; and (3) independent validation on a large set of plasma from 90 patients with CRC, 20 patients with gastric cancer, 20 patients with inflammatory bowel disease (IBD) and 50 healthy controls. RESULTS: Of the panel of 95 miRNAs analysed, five were upregulated both in plasma and tissue samples. All the five miRNAs were validated on the plasma of 25 patients with CRC and 20 healthy controls. Both miR-17-3p and miR-92 were significantly elevated in the patients with CRC (p<0.0005). The plasma levels of these markers were significantly reduced after surgery in 10 patients with CRC (p<0.05). Further validation with an independent set of plasma samples (n = 180) indicated that miR-92 differentiates CRC from gastric cancer, IBD and normal subjects. This marker yielded a receiver operating characteristic curve area of 88.5%. At a cut-off of 240 (relative expression in comparison to RNU6B snRNA), the sensitivity was 89% and the specificity was 70% in discriminating CRC from control subjects. CONCLUSION: MiR-92 is significantly elevated in plasma of patients with CRC and can be a potential non-invasive molecular marker for CRC screening.

Accident and Emergency Medicine Academic Unit, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Cell-free fetal DNA is present in the plasma of pregnant women. It consists of short DNA fragments among primarily maternally derived DNA fragments. We sequenced a maternal plasma DNA sample at up to 65-fold genomic coverage. We showed that the entire fetal and maternal genomes were represented in maternal plasma at a constant relative proportion. Plasma DNA molecules showed a predictable fragmentation pattern reminiscent of nuclease-cleaved nucleosomes, with the fetal DNA showing a reduction in a 166-base pair (bp) peak relative to a 143-bp peak, when compared with maternal DNA. We constructed a genome-wide genetic map and determined the mutational status of the fetus from the maternal plasma DNA sequences and from information about the paternal genotype and maternal haplotype. Our study suggests the feasibility of using genome-wide scanning to diagnose fetal genetic disorders prenatally in a noninvasive way.

BACKGROUND: Biventricular pacing has been proposed to improve symptoms and exercise capacity in patients with advanced heart failure and wide electrocardiographic wave complexes. This study investigated the effect of biventricular pacing on reverse remodeling and the underlying mechanisms. METHODS AND RESULTS: Twenty-five patients with NYHA class III to IV heart failure and electrocardiographic wave complex duration >140 ms receiving biventricular pacing therapy were assessed serially up to 3 months after pacing and when pacing was withheld for 4 weeks. Tissue Doppler echocardiography was performed using a 6-basal, 6-mid segmental model to assess the time to peak sustained systolic contraction (T(S)). There was significant improvement of ejection fraction, dP/dt, and myocardial performance index; decrease in mitral regurgitation, left ventricular (LV) end-diastolic (205+/-68 versus 168+/-67 mL, P<0.01) and end-systolic volume (162+/-54 versus 122+/-42 mL, P<0.01); and improved 6-minute hall-walk distance and quality of life score after pacing for 3 months. The mechanisms of benefits were as follows: (1) improved LV synchrony, as evident by homogeneous delay of T(S) to a timing close to the latest (usually the lateral) segment abolishing the intersegmental difference in T(S) and decreasing the standard deviation of T(S) within the left ventricle (37.7+/-10.9 versus 29.3+/-8.3 ms, P<0.05); (2) improved interventricular synchrony; and (3) shortened isovolumic contraction time (122+/-57 versus 82+/-36 ms, P<0.05) but increased diastolic filling time. These benefits are pacing dependent, because withholding the pacing resulted in varying speeds in the loss of cardiac improvements. CONCLUSIONS: Biventricular pacing reverses LV remodeling and improves cardiac function. Improvement of LV mechanical synchrony seems to be the predominant mechanism.