St George’s University Hospitals NHS Foundation Trust

IMPORTANCE: The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. OBSERVATIONS: SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. CONCLUSIONS AND RELEVANCE: As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1 ). It is a condition, which can have long-term consequences (after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1 ) beyond which the seizure should be regarded as "continuous seizure activity." The second time point (t2 ) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.

BACKGROUND: Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. METHODS: We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. RESULTS: We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. CONCLUSIONS: In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

Importance: Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. Objective: To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. Design, Setting, and Participants: In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. Exposures: COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. Main Outcomes and Measures: The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. Results: A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. Conclusions and Relevance: In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

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.

BACKGROUND: The COVID-19 pandemic has had a profound impact on health-care systems and potentially on pregnancy outcomes, but no systematic synthesis of evidence of this effect has been undertaken. We aimed to assess the collective evidence on the effects on maternal, fetal, and neonatal outcomes of the pandemic. METHODS: We did a systematic review and meta-analysis of studies on the effects of the pandemic on maternal, fetal, and neonatal outcomes. We searched MEDLINE and Embase in accordance with PRISMA guidelines, from Jan 1, 2020, to Jan 8, 2021, for case-control studies, cohort studies, and brief reports comparing maternal and perinatal mortality, maternal morbidity, pregnancy complications, and intrapartum and neonatal outcomes before and during the pandemic. We also planned to record any additional maternal and offspring outcomes identified. Studies of solely SARS-CoV-2-infected pregnant individuals, as well as case reports, studies without comparison groups, narrative or systematic literature reviews, preprints, and studies reporting on overlapping populations were excluded. Quantitative meta-analysis was done for an outcome when more than one study presented relevant data. Random-effects estimate of the pooled odds ratio (OR) of each outcome were generated with use of the Mantel-Haenszel method. This review was registered with PROSPERO (CRD42020211753). FINDINGS: =26%; three studies, 37 and 272 pregnancies). No overall significant effects were identified for other outcomes included in the quantitative analysis: maternal gestational diabetes; hypertensive disorders of pregnancy; preterm birth before 34 weeks', 32 weeks', or 28 weeks' gestation; iatrogenic preterm birth; labour induction; modes of delivery (spontaneous vaginal delivery, caesarean section, or instrumental delivery); post-partum haemorrhage; neonatal death; low birthweight (<2500 g); neonatal intensive care unit admission; or Apgar score less than 7 at 5 min. INTERPRETATION: Global maternal and fetal outcomes have worsened during the COVID-19 pandemic, with an increase in maternal deaths, stillbirth, ruptured ectopic pregnancies, and maternal depression. Some outcomes show considerable disparity between high-resource and low-resource settings. There is an urgent need to prioritise safe, accessible, and equitable maternity care within the strategic response to this pandemic and in future health crises. FUNDING: None.

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).

BACKGROUND: Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. METHODS: This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. RESULTS: We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. CONCLUSIONS: Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

BACKGROUND: Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS: We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS: From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. CONCLUSIONS: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.

The purpose of this chapter is to assist in the use and interpretation of intrapartum cardiotocography (CTG), as well as in the clinical management of specific CTG patterns. In the preparation of these guidelines, it has been assumed that all necessary resources, both human and material, required for intrapartum monitoring and clinical management are readily available. Unexpected complications may occur during labor, even in patients without prior evidence of risk, so maternity hospitals need to ensure the presence of trained staff, as well as appropriate facilities and equipment for an expedite delivery (in particular emergency cesarean delivery). CTG monitoring should never be regarded as a substitute for good clinical observation and judgement, or as an excuse for leaving the mother unattended during labor. The evidence for the benefits of continuous CTG monitoring, as compared with intermittent auscultation, in both low- and high-risk labors is scientifically inconclusive [1,2]. When compared with intermittent auscultation, continuous CTG has been shown to decrease the occurrence of neonatal seizures, but no effect has been demonstrated on the incidence of overall perinatal mortality or cerebral palsy. However, these studies were carried out in the 1970s, 1980s, and early 1990s where equipment, clinical experience, and interpretation criteria were very different from current practice, and they were clearly underpowered to evaluate differences in major outcomes [3]. These issues are discussed in more detail in Section 8 of this chapter. In spite of these limitations, most experts believe that continuous CTG monitoring should be considered in all situations where there is a high risk of fetal hypoxia/acidosis, whether due to maternal health conditions (such as vaginal hemorrhage and maternal pyrexia), abnormal fetal growth during pregnancy, epidural analgesia, meconium stained liquor, or the possibility of excessive uterine activity, as occurs with induced or augmented labor. Continuous CTG is also recommended when abnormalities are detected during intermittent fetal auscultation. The use of continuous intrapartum CTG in low-risk women is more controversial, although it has become standard of care in many countries. An alternative approach is to provide intermittent CTG monitoring alternating with fetal heart rate (FHR) auscultation. There is some evidence to support that this is associated with similar neonatal outcomes in low-risk pregnancies [4]. Intermittent monitoring should be carried out long enough to allow adequate evaluation of the basic CTG features (see below). The routine use of admission CTG for low-risk women on entrance to the labor ward has been associated with an increase in cesarean delivery rates and no improvement in perinatal outcomes [5], but studies were also underpowered to show such differences. In spite of the lack of evidence regarding benefit, this procedure has also become standard of care in many countries. Maternal supine recumbent position can result in aortocaval compression by the pregnant uterus, affecting placental perfusion and fetal oxygenation. Prolonged monitoring in this position should therefore be avoided. The lateral recumbent, half-sitting, and upright positions are preferable alternatives [6]. CTG acquisition can be performed by portable sensors that transmit signals wirelessly to a remote fetal monitor (telemetry). This solution has the advantage of allowing the mother to move freely during signal acquisition, rather than be restrained to bed or a sofa, and should therefore be the preferred option when available. Telemetry systems differ in the maximum distance allowed between patient and monitor for adequate signal transmission [7]. The horizontal scale for CTG registration and viewing is commonly called “paper speed” and available options are usually 1, 2, or 3 cm/min. In many countries throughout the world 1 cm/min is selected, while in the Netherlands it is usually 2 cm/min, and in North America and Japan it is almost exclusively 3 cm/min. Some experts feel that 1 cm/min provides records of sufficient detail for clinical analysis, and this has the advantage of reducing tracing length. Other experts feel that the small details of CTG tracings are better evaluated using higher papers speeds. The vertical scale used for registration and viewing may also be different, and available alternatives are 20 or 30 bpm/cm. The paper scales used in each center should be the ones with which healthcare professionals are most familiar, because tracing interpretation depends on pattern recognition and these patterns may appear very different. Inadvertent use of paper scales to which the staff is unaccustomed may lead to erroneous interpretations of CTG features. For example, at 3 cm/min variability appears reduced to a clinician familiar with the 1 cm/min scale, while it may appear exaggerated in the opposite situation (see examples below). External FHR monitoring uses a Doppler ultrasound transducer to detect the movement of cardiac structures. The resulting signal requires signal modulation and autocorrelation to provide adequate quality recordings [8]. This process results in an approximation of the true heart rate intervals, but this is considered to be sufficiently accurate for analysis. External FHR monitoring is more prone to signal loss, to inadvertent monitoring of the maternal heart rate (Fig. 1) [9], and to signal artefacts such as double-counting (Fig. 2) and half-counting [8], particularly during the second stage of labor. It may also not record fetal cardiac arrhythmias accurately. Maternal heart rate monitoring in the last 9 minutes of the tracing. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Double-counting of the fetal heart rate during decelerations (arrows). External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Internal FHR monitoring using a fetal electrode (usually known as scalp electrode, but it can also be applied to the breech) evaluates the time intervals between successive heart beats by identifying R waves on the fetal electrocardiogram QRS complex, and therefore measures ventricular depolarization cycles. This method provides a more accurate evaluation of intervals between cardiac cycles, but it is more expensive because it requires a disposable electrode. It is very important that the fetal electrode is only applied after a clear identification of the presenting part and that delicate fetal structures such as the sutures and fontanels are avoided. Internal FHR monitoring requires ruptured membranes and has established contraindications, mainly related to the increased risk of vertical transmission of infections. It should not be used in patients with active genital herpes infection, those who are seropositive to hepatitis B, C, D, E, or to HIV [10,11], in suspected fetal blood disorders, when there is uncertainty about the presenting part, or when artificial rupture of membranes is inappropriate (i.e. an unengaged presentation). Fetal electrode placement should also preferably be avoided in very preterm fetuses (under 32 weeks of gestation). External FHR monitoring is the recommended initial method for routine intrapartum monitoring, provided that a recording of acceptable quality is obtained, i.e. that the basic CTG features can be identified. Minimum requirements for using this method are that careful repositioning of the probe is carried out during the second stage of labor, that in all atypical FHR tracings maternal heart rate monitoring is ruled out (see below), and if any doubt remains, fetal auscultation, ultrasound evaluation, or internal FHR monitoring are performed. If an acceptable record cannot be obtained with external monitoring or if a cardiac arrhythmia is suspected, then internal monitoring should be used, in the absence of the previously mentioned contraindications. External monitoring of uterine contractions using a tocodynamometer (toco) evaluates increased myometrial tension measured through the abdominal wall. Incorrect placement, reduced tension applied to the supporting elastic band, or abdominal adiposity may result in failed or inadequate registration of contractions. In addition, this technology only provides accurate information on the frequency of contractions. It is not possible to extract reliable information regarding the intensity and duration of contractions, nor on basal uterine tone. Internal monitoring of uterine contractions using an intrauterine catheter provides quantitative information on the intensity and duration of contractions, as well as on basal uterine tone, but it is more expensive as the catheter is disposable, and requires ruptured membranes. Contraindications include uterine hemorrhage of unknown cause and placenta previa. It may also be associated with a small risk of fetal injury, placental hemorrhage, uterine perforation, and infection [12]. The routine use of intrauterine pressure catheters has not been shown to be associated with improved outcomes in induced and augmented labor [13], and so it is not recommended for routine clinical use. Simultaneous monitoring of the maternal heart rate (MHR) can be useful in specific maternal health conditions and in cases where it is difficult to distinguish between maternal and fetal heart rates (for example complete fetal heart block) [9]. Some CTG monitors provide the possibility of continuous MHR monitoring, either by electrocardiography or pulse oximetry. In some recent models, the latter technology has been incorporated in the tocodynamometer, allowing continuous MHR monitoring without the use of additional equipment. Providing that the technology is available and does not cause discomfort to the mother, simultaneous MHR monitoring should be considered when performing continuous CTG, especially during the second stage of labor, when tracings show accelerations coinciding with contractions and expulsive efforts [9], or when the MHR is elevated. Continuous external FHR monitoring of twin gestations during labor should preferably be performed with dual channel monitors that allow simultaneous monitoring of both FHRs, as duplicate monitoring of the same twin may occur and this can be picked up by observing almost identical tracings. Some monitors have embedded algorithms to alarm when this situation is suspected. During the second stage of labor, external FHR monitoring of twins is particularly affected by signal loss, and for this reason some experts believe that the presenting twin should preferably be monitored internally for better signal quality [14], if no contraindications to fetal electrode placement are present. Other experts believe that external monitoring of both twins is acceptable, provided that distinct and good quality FHR signals can be obtained. All CTG tracings need to be identified with the patient name, place of recording, “paper speed,” and date and time when acquisition started and ended. In hospitals where paper CTG recordings are used, the latter should be considered as part of the patient record and preserved as such. In hospitals using digital CTG archives [15], a secure file backup system needs to be in place, and all tracings should be readily available for review by the clinical staff. CTG analysis starts with the evaluation of basic CTG features (baseline, variability, accelerations, decelerations, and contractions) followed by overall CTG classification. This is the mean level of the most horizontal and less oscillatory FHR segments. It is estimated in time periods of 10 minutes and expressed in beats per minute (bpm). The baseline value may vary between subsequent 10-minute sections. Normal baseline: a value between 110 and 160 bpm. Fetal behavioral state of active wakefulness. This pattern may lead to erroneously high baseline estimation if it is identified at the top of accelerations. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Preterm fetuses tend to have values toward the upper end of this range and post-term fetuses towards the lower end. Some experts consider the normal baseline values at term to be between 110-150 bpm. Tachycardia: a baseline value above 160 bpm lasting more than 10 minutes. Maternal pyrexia is the most frequent cause of fetal tachycardia, and it may be of extrauterine origin or associated with intrauterine infection. Epidural analgesia may also cause a rise in maternal temperature resulting in fetal tachycardia [17]. In the initial stages of a nonacute fetal hypoxemia, catecholamine secretion may also result in tachycardia. Other less frequent causes are the administration of beta-agonist drugs [18] (salbutamol, terbutaline, ritodrine, fenoterol), parasympathetic blockers (atropine, scopolamine), and fetal arrhythmias such as supraventricular tachycardia and atrial flutter. Bradycardia: a baseline value below 110 bpm lasting more than 10 minutes. Values between 100 and 110 bpm may occur in normal fetuses, especially in postdate pregnancies. Maternal hypothermia [19], administration of beta-blockers [20], and fetal arrhythmias such as atrioventricular block are other possible causes. Normal variability: a bandwidth amplitude of 5−25 bpm. Reduced variability: a bandwidth amplitude below 5 bpm for more than 50 minutes in baseline segments [21] (4, 5), or for more than 3 minutes during decelerations [22] (see 8, 9). Reduced variability. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Reduced variability. The baseline is affected by contractions causing decreases in fetal heart rate that are close to fulfilling the criteria for decelerations, but the bandwidth remains reduced. Internal fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Reduced variability can occur due to central nervous system hypoxia/acidosis and resulting decreased sympathetic and parasympathetic activity, but it can also be due to previous cerebral injury [23], infection, administration of central nervous system depressants or parasympathetic blockers. During deep sleep, variability is usually in the lower range of normality, but the bandwidth amplitude is seldom under 5 bpm. There is a high degree of subjectivity in the visual evaluation of this and therefore careful is recommended in an normal CTG, reduced variability due to is very to occur during labor without or decelerations and a rise in the variability a bandwidth value bpm lasting more than 30 minutes (Fig. variability: Internal fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). The of this pattern is but it may be with decelerations, when hypoxia/acidosis very It is to be by fetal system to in less than 30 in FHR above the of more than bpm in and lasting more than but less than 10 minutes. accelerations with fetal and are a of a that does not have 32 weeks of amplitude and frequency may be lower and 10 bpm of with the of fetal behavioral accelerations occur during periods of deep sleep, which can last up to 50 minutes The absence of accelerations in an normal intrapartum CTG is of but it is to coinciding with uterine contractions, especially in the second stage of labor, possible erroneous recording of the maternal heart the FHR more with a while the maternal heart rate [9]. decelerations that are with normal variability the and are with contractions. are to be by fetal compression and not fetal decelerations decelerations that a to in less than 30 good variability the to the and to uterine contractions (Fig. Internal fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). decelerations the of decelerations during labor, and they a to increased as occurs with compression are seldom associated with an important degree of fetal hypoxia/acidosis, they to a reduced variability the (see decelerations below), duration 3 minutes (see decelerations below). decelerations with reduced decelerations with a a to the baseline reduced variability the (Fig. and occurs when more than 30 between the of a and When contractions are decelerations more than 20 after the of a have a after the and a to the baseline after the end of the decelerations in the second of the tracing. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). These decelerations are of a to fetal In the presence of a tracing with no accelerations and reduced variability, the of decelerations also those with an amplitude of bpm. Prolonged lasting more than 3 minutes. These are to include a and to 5 with FHR at less than bpm and reduced variability the (Fig. are associated with fetal hypoxia/acidosis and Prolonged External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). a with an amplitude of and a frequency of per This pattern more than 30 and with accelerations (Fig. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). The of the pattern is but it occurs in with fetal as is in hemorrhage, and ruptured previa. It has also been in cases of fetal infection, cardiac and pattern the but with a more rather than the (Fig. duration seldom 30 minutes and it is by normal patterns and External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). This pattern has been after administration to the mother, and during periods of fetal and other It is difficult to distinguish the pattern from the true leaving the duration of the as the most important to between the This to periods of fetal deep alternating with periods of active and The occurrence of different behavioral is a of fetal and absence of can last up to 50 minutes [21] and is associated with a very accelerations, and variability. is the most frequent behavioral and is by a of accelerations and normal variability. is and by a of accelerations and normal variability (Fig. In the latter accelerations may be so frequent as to cause in baseline estimation (see between the different patterns become after weeks of to fetal nervous system These are in the uterine signal followed by with in This an excessive frequency of contractions and is as the occurrence of more than contractions in 10 in successive 10-minute or a requires a previous evaluation of basic CTG features (see should be of or to the criteria in Other systems a of are recommended by some experts to the of CTG signals during labor, of the tracing should be carried out at 30 minutes. and to the mother, can FHR features (see so CTG analysis needs to be with other clinical information for a interpretation and adequate a if the to a baseline and a variability, the risk of to the central is very However, the that should clinical management are in When fetal hypoxia/acidosis is or suspected and and is required to neonatal this does not mean an cesarean delivery or vaginal The cause for the of the pattern can be identified and the situation with subsequent of adequate fetal and the to a normal tracing. uterine is the most frequent cause of fetal hypoxia/acidosis and it can be detected by in the CTG tracing the uterine It can usually be by reducing or if with (salbutamol, terbutaline, or During the second stage of labor, maternal efforts can also to fetal hypoxia/acidosis and the mother can be to the situation is compression can occur in the supine position and lead to reduced placental uterine may also be associated with the supine position due to the of the by the uterine In these the mother to is followed by of the CTG compression is cause of CTG and these can be by the maternal position or by performing maternal can also occur during labor, usually after epidural or analgesia and it is usually by administration an Other less frequent complications affecting the maternal maternal or the fetal can also result in fetal hypoxia/acidosis and management is the of this administration to the mother is used with the of fetal and CTG but there is no evidence from clinical that this when performed in is when maternal is adequate are also commonly used for the purpose of CTG but there is no evidence from clinical to that this is in women clinical is required to the cause for a or CTG, to the of the conditions with which it is and to the of with the of fetal hypoxia/acidosis, as well as may be used to evaluate fetal When a or CTG pattern is the cause should be a tracing If the situation does not and the pattern to needs to be for evaluation or delivery if a pattern During the second stage of labor, due to the additional effect of maternal hypoxia/acidosis may more should be to the of maternal and if there is no delivery should be has limitations, and it is necessary to be of these for use of the It has been well demonstrated that CTG analysis is to and even when use The that are prone to are the identification and of decelerations, the evaluation of variability and the of tracings as and The subjectivity of analysis has also been demonstrated in of where CTG features are to be more abnormal in cases with known neonatal studies have evaluated the of and to the occurrence of CTG interpretation different intervals between tracing and and different criteria to have been used, resulting in However, it is that hypoxia/acidosis has not been after a normal CTG tracing. the other and tracings have a to and i.e. a of cases with and tracings not have these outcomes there is a between FHR patterns and hypoxia/acidosis, to between with or without is they are but have a and However, it should not be that the of intrapartum fetal monitoring is to situations that so as to fetal The subjectivity of CTG interpretation and the that is a that may not the of or injury are important to these of have been continuous CTG monitoring with intermittent as for fetal hypoxia/acidosis during labor, in both low- and high-risk women [1,2]. However, these place in the 1970s, 1980s, and early and used different CTG interpretation so it is difficult to results to current clinical these in they a of continuous CTG for fetal monitoring in all women during labor, as the only improvement a in neonatal not evaluated in most and no differences were in the of overall perinatal mortality and cerebral palsy. However, it is that the were underpowered to detect differences in these outcomes [3]. a small of perinatal and cerebral are by intrapartum hypoxia/acidosis, so a of cases are to show any the other continuous CTG associated with a increase in cesarean delivery and a increase in vaginal additional for the mother and and the may result from CTG of the of fetal and inadequate clinical It is for clinical need to be as and as to allow even in and In addition, and of the labor ward staff is to ensure use of this The have no of to

### What you need to know Advances in cancer treatments mean that half of people now diagnosed with cancer can expect to survive for at least 10 years,1 defining many cancers as long term conditions. Psychiatric illnesses such as depression and anxiety are common, but often neglected, complications of cancer, influencing quality of life, adherence to treatment, cancer survival, and treatment costs.23 Depression and anxiety affect up to 20% and 10% of patients with cancer respectively, regardless of the point in the cancer trajectory, and whether in curative or palliative treatment.4 Geographical variations in the diagnosis and treatment of depression or anxiety in cancer settings implies under-recognition of these problems.5 Depression is associated with poor adherence to cancer treatment and poor cancer survival,6 and the increased risk of suicide in all patients with cancer7 is a concern. This clinical update outlines the prevalence, aetiology, and management of depression and anxiety in patients with cancer to raise awareness among doctors of the need to address the psychiatric consequences of cancer. ### Sources and selection criteria We conducted tumour-specific and treatment-specific PubMed searches, and used NICE …

BACKGROUND: IBS affects 5-11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. AIM: To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. METHODS: Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. RESULTS: Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients' concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT(3) antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT(4) agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. CONCLUSIONS: Better ways of identifying which patients will respond to specific treatments are urgently needed.

OBJECTIVE: Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. METHODS: C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R(-/-)) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. RESULTS: Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1beta transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1beta, both in mice pretreated with IL-1 receptor antagonist and in IL-1R(-/-) mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. INTERPRETATION: A peripheral surgery-induced innate immune response triggers an IL-1beta-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.

In the 20th century, the development, licensing and implementation of vaccines as part of large, systematic immunization programs started to address health inequities that existed globally. However, at the time of writing, access to vaccines that prevent life-threatening infectious diseases remains unequal to all infants, children and adults in the world. This is a problem that many individuals and agencies are working hard to address globally. As clinicians and biomedical scientists we often focus on the health benefits that vaccines provide, in the prevention of ill-health and death from infectious pathogens. Here we discuss the health, economic and social benefits of vaccines that have been identified and studied in recent years, impacting all regions and all age groups. After learning of the emergence of SARS-CoV-2 virus in December 2019, and its potential for global dissemination to cause COVID-19 disease was realized, there was an urgent need to develop vaccines at an unprecedented rate and scale. As we appreciate and quantify the health, economic and social benefits of vaccines and immunization programs to individuals and society, we should endeavor to communicate this to the public and policy makers, for the benefit of endemic, epidemic, and pandemic diseases.

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

BACKGROUND: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.

INTRODUCTION The “sepsis bundle” has been central to the implementation of the Surviving Sepsis Campaign (SSC) from the first publication of its evidence-based guidelines in 2004 through subsequent editions (1–6). Developed separately from the guidelines publication by the SSC, the bundles have been the cornerstone of sepsis quality improvement since 2005 (7–11). As noted when they were introduced, the bundle elements were designed to be updated as indicated by new evidence and have evolved accordingly. In response to the publication of “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016” (12,13), a revised “hour-1 bundle” has been developed and is presented below (Fig. 1).Figure 1.: Hour-1 Surviving Sepsis Campaign Bundle of Care.*The compelling nature of the evidence in the literature, which has demonstrated an association between compliance with bundles and improved survival in patients with sepsis and septic shock, led to the adoption of the SSC measures by the National Quality Forum (NQF) and subsequently both by the New York State (NYS) Department of Health (14) and the Centers for Medicare and Medicaid Services (CMS) (15) in the USA for mandated public reporting. The important relationship between the bundles and survival was confirmed in a publication from this NYS initiative (16). Paramount in the management of patients with sepsis is the concept that sepsis is a medical emergency. As with polytrauma, acute myocardial infarction, and stroke, early identification and appropriate immediate management in the initial hours after development of sepsis improves outcomes (7–11,14,16–21). The guidelines state that these patients need urgent assessment and treatment, including initial fluid resuscitation while pursuing source control, obtaining further laboratory results, and attaining more precise measurements of hemodynamic status. A guiding principle is that these complex patients need a detailed initial assessment and then ongoing re-evaluation of their response to treatment. The elements of the 2018 bundle, intended to be initiated within the first hour, are listed in Table 1 and presented in the following. Consistent with previous iterations of the SSC sepsis bundles, “time zero” or “time of presentation” is defined as the time of triage in the emergency department or, if referred from another care location, from the earliest chart annotation consistent with all elements of sepsis (formerly severe sepsis) or septic shock ascertained through chart review. Because this new bundle is based on the 2016 Guidelines publication, the guidelines themselves should be referred to for further discussion and evidence related to each element and to sepsis management as a whole.TABLE 1.: Bundle Elements With Strength of Recommendations and Under-Pinning Quality of Evidence (12 , 13)HOUR-1 BUNDLE The most important change in the revision of the SSC bundles is that the 3-h and 6-h bundles have been combined into a single “hour-1 bundle” with the explicit intention of beginning resuscitation and management immediately. We believe this reflects the clinical reality at the bedside of these seriously ill patients with sepsis and septic shock—that clinicians begin treatment immediately, especially in patients with hypotension, rather than waiting or extending resuscitation measures over a longer period. More than 1 hour may be required for resuscitation to be completed, but initiation of resuscitation and treatment, such as obtaining blood for measuring lactate and blood cultures, administration of fluids and antibiotics, and in the case of life-threatening hypotension, initiation of vasopressor therapy, are all begun immediately. It is also important to note that there are no published studies that have evaluated the efficacy in important subgroups, including burns and immunocompromised patients. This knowledge gap needs to be addressed in future studies specifically targeting these subgroups. The elements included in the revised bundle are taken from the Surviving Sepsis Campaign Guidelines, and the level of evidence in support of each element can be seen in Table 1 (12, 13). We believe the new bundle is an accurate reflection of actual clinical care. Measure Lactate Level While serum lactate is not a direct measure of tissue perfusion (22), it can serve as a surrogate, as increases may represent tissue hypoxia, accelerated aerobic glycolysis driven by excess beta-adrenergic stimulation, or other causes associated with worse outcomes (23). Randomized controlled trials have demonstrated a significant reduction in mortality with lactate-guided resuscitation (24–28). If initial lactate is elevated (> 2mmol/L), it should be remeasured within 2−4 h to guide resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion (24). Obtain Blood Cultures Prior to Antibiotics Sterilization of cultures can occur within minutes of the first dose of an appropriate antimicrobial (29,30), so cultures must be obtained before antibiotic administration to optimize the identification of pathogens and improve outcomes (31,32). Appropriate blood cultures include at least two sets (aerobic and anaerobic). Administration of appropriate antibiotic therapy should not be delayed in order to obtain blood cultures. Administer Broad-Spectrum Antibiotics Empiric broad-spectrum therapy with one or more intravenous antimicrobials to cover all likely pathogens should be started immediately (21) for patients presenting with sepsis or septic shock. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established, or discontinued if a decision is made that the patient does not have infection. The link between early administration of antibiotics for suspected infection and antibiotic stewardship remains an essential aspect of high-quality sepsis management. If infection is subsequently proven not to exist, then antimicrobials should be discontinued. Administer IV Fluid Early effective fluid resuscitation is crucial for the stabilization of sepsis-induced tissue hypoperfusion or septic shock. Given the urgent nature of this medical emergency, initial fluid resuscitation should begin immediately upon recognizing a patient with sepsis and/or hypotension and elevated lactate, and completed within 3 hours of recognition. The guidelines recommend this should comprise a minimum of 30 mL/kg of intravenous crystalloid fluid. Although little literature includes controlled data to support this volume, recent interventional studies have described this as usual practice in the early stages of resuscitation, and observational evidence is supportive (7,8). The absence of any clear benefit following the administration of colloid compared with crystalloid solutions in the combined subgroups of sepsis, in conjunction with the expense of albumin, supports a strong recommendation for the use of crystalloid solutions in the initial resuscitation of patients with sepsis and septic shock. Because some evidence indicates that a sustained positive fluid balance during ICU stay is harmful (33–37), fluid administration beyond initial resuscitation requires careful assessment of the likelihood that the patient remains fluid responsive. Apply Vasopressors Urgent restoration of an adequate perfusion pressure to the vital organs is a key part of resuscitation. This should not be delayed. If blood pressure is not restored after initial fluid resuscitation, then vasopressors should be commenced within the first hour to achieve mean arterial pressure (MAP) of ≥ 65 mm Hg. The physiologic effects of vasopressors and combined inotrope/vasopressor selection in septic shock are outlined in a large number of literature reviews (38–47). SUMMARY Previous iterations of the sepsis bundle were introduced as a means of providing education and improvement related to sepsis management. The literature supports the use of sepsis bundles for improving outcomes in patients with sepsis and septic shock. This new sepsis “hour-1 bundle,” based on the 2016 guidelines, should be introduced to emergency department, floor, and ICU staff as the next iteration of ever-improving tools in the care of patients with sepsis and septic shock as we all work to lessen the global burden of sepsis. ACKNOWLEDGMENTS The authors gratefully acknowledge Deb McBride and Lori Harmon for their invaluable assistance with manuscript preparation and editing (D.M.) and overall support for this work (D.M. and L.H.).