Johannesburg Hospital

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 ICU admission, we suggest admitting the patients to the ICU within 6 hr. Weak , low quality of evidence INFECTION 11. For adults with suspected sepsis or septic shock but unconfirmed infection, we recommend continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected. Best practice statement 12. For adults with possible septic shock or a high likelihood for sepsis, we recommend administering antimicrobials immediately, ideally within 1 hr of recognition. Strong , low quality of evidence (Septic shock) CHANGED from previous: "We recommend that administration of intravenous antimicrobials should be initiated as soon as possible after recognition and within one hour for both a) septic shock and b) sepsis without shock" Strong , very low quality of evidence (Sepsis without shock) strong recommendation , moderate quality of evidence 13. For adults with possible sepsis without shock, we recommend rapid assessment of the likelihood of infectious versus noninfectious causes of acute illness. Best practice statement 14. For adults with possible sepsis without shock, we suggest a time-limited course of rapid investigation and if concern for infection persists, the administration of antimicrobials within 3 hr from the time when sepsis was first recognized. Weak , very low quality of evidence NEW from previous: "We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock" strong recommendation , moderate quality of evidence 15. For adults with a low likelihood of infection and without shock, we suggest deferring antimicrobials while continuing to closely monitor the patient. Weak , very low quality of evidence NEW from previous: "We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within 1 hr for both a) septic shock and b) sepsis without shock" strong recommendation , moderate quality of evidence 16. For adults with suspected sepsis or septic shock, we suggest against using procalcitonin plus clinical evaluation to decide when to start antimicrobials, as compared to clinical evaluation alone. Weak , very low quality of evidence 17. For adults with sepsis or septic shock at high risk of MRSA, we recommend using empiric antimicrobials with MRSA coverage over using antimicrobials without MRSA coverage. Best practice statement NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 18. For adults with sepsis or septic shock at low risk of MRSA, we suggest against using empiric antimicrobials with MRSA coverage, as compared with using antimicrobials without MRSA coverage. Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 19. For adults with sepsis or septic shock and high risk for multidrug resistant (MDR) organisms, we suggest using two antimicrobials with gram-negative coverage for empiric treatment over one gram-negative agent. Weak , very low quality of evidence 20. For adults with sepsis or septic shock and low risk for multidrug resistant (MDR) organisms, we suggest against using two gram-negative agents for empiric treatment, as compared to one gram-negative agent. Weak , very low quality of evidence 21. For adults with sepsis or septic shock, we suggest against using double gram-negative coverage once the causative pathogen and the susceptibilities are known. Weak , very low quality of evidence 22. For adults with sepsis or septic shock at high risk of fungal infection, we suggest using empiric antifungal therapy over no antifungal therapy. Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage." Strong recommendation , moderate quality of evidence 23. For adults with sepsis or septic shock at low risk of fungal infection, we suggest against empiric use of antifungal therapy Weak , low quality of evidence NEW from previous: "We recommend empiric broad-spectrum therapy with one or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage. " Strong recommendation , moderate quality of evidence 24. We make no recommendation on the use of antiviral agents. No recommendation 25. For adults with sepsis or septic shock, we suggest using prolonged infusion of beta-lactams for maintenance (after an initial bolus) over conventional bolus infusion. Weak , moderate-quality evidence 26. For adults with sepsis or septic shock, we recommend optimising dosing strategies of antimicrobials based on accepted pharmacokinetic/pharmacodynamic (PK/PD) principles and specific drug properties. Best practice statement 27. For adults with sepsis or septic shock, we recommend rapidly identifying or excluding a specific anatomical diagnosis of infection that requires emergent source control and implementing any required source control intervention as soon as medically and logistically practical. Best practice statement 28. For adults with sepsis or septic shock, we recommend prompt removal of intravascular access devices that are a possible source of sepsis or septic shock after other vascular access has been established. Best practice statement 29. For adults with sepsis or septic shock, we suggest daily assessment for de-escalation of antimicrobials over using fixed durations of therapy without daily reassessment for de-escalation. Weak , very low quality of evidence 30. For adults with an initial diagnosis of sepsis or septic shock and adequate source control, we suggest using shorter over longer duration of antimicrobial therapy. Weak , very low quality of evidence 31. For adults with an initial diagnosis of sepsis or septic shock and adequate source control where optimal duration of therapy is unclear, we suggest using procalcitonin AND clinical evaluation to decide when to discontinue antimicrobials over clinical evaluation alone. Weak , low quality of evidence HEMODYNAMIC MANAGEMENT 32. For adults with sepsis or septic shock, we recommend using crystalloids as first-line fluid for resuscitation. Strong , moderate-quality evidence 33. For adults with sepsis or septic shock, we suggest using balanced crystalloids instead of normal saline for resuscitation. Weak , low quality of evidence CHANGED from weak recommendation , low quality of evidence. "We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock" 34. For adults with sepsis or septic shock, we suggest using albumin in patients who received large volumes of crystalloids. Weak , moderate-quality evidence 35. For adults with sepsis or septic shock, we recommend against using starches for resuscitation. Strong , high-quality evidence 36. For adults with sepsis and septic shock, we suggest against using gelatin for resuscitation. Weak , moderate-quality evidence UPGRADE from weak recommendation , low quality of evidence "We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock." 37. For adults with septic shock, we recommend using norepinephrine as the first-line agent over other vasopressors. Strong Dopamine. High-quality evidence Vasopressin. Moderate-quality evidence Epinephrine. Low quality of evidence Selepressin. Low quality of evidence Angiotensin II. Very low-quality evidence 38. For adults with septic shock on norepinephrine with inadequate mean arterial pressure levels, we suggest adding vasopressin instead of escalating the dose of norepinephrine. Weak , moderate quality evidence 39. For adults with septic shock and inadequate mean arterial pressure levels despite norepinephrine and vasopressin, we suggest adding epinephrine. Weak , low quality of evidence 40. For adults with septic shock, we suggest against using terlipressin. Weak , low quality of evidence 41. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest either adding dobutamine to norepinephrine or using epinephrine alone. Weak , low quality of evidence 42. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest against using levosimendan. Weak , low quality of evidence NEW 43. For adults with septic shock, we suggest invasive monitoring of arterial blood pressure over noninvasive monitoring, as soon as practical and if resources are available. Weak , very low quality of evidence 44. For adults with septic shock, we suggest starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured. Weak , very low quality of evidence NEW 45. There is insufficient evidence to make a recommendation on the use of restrictive versus liberal fluid strategies in the first 24 hr of resuscitation in patients with sepsis and septic shock who still have signs of hypoperfusion and volume depletion after the initial resuscitation. No recommendation NEW "We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock" Weak recommendation , low quality of evidence "We suggest using crystalloids over gelatins when resuscitating patients with sepsis or septic shock." Weak recommendation , low quality of evidence VENTILATION 46.There is insufficient evidence to make a recommendation on the use of conservative oxygen targets in adults with sepsis-induced hypoxemic respiratory failure. No recommendation 47. For adults with sepsis-induced hypoxemic respiratory failure, we suggest the use of high flow nasal oxygen over noninvasive ventilation. Weak , low quality of evidence NEW 48. There is insufficient evidence to make a recommendation on the use of noninvasive ventilation in comparison to invasive ventilation for adults with sepsis-induced hypoxemic respiratory failure. No recommendation 49. For adults with sepsis-induced ARDS, we recommend using a low tidal volume ventilation strategy (6 mL/kg), over a high tidal volume strategy (> 10 mL/kg). Strong , high-quality evidence 50. For adults with sepsis-induced severe ARDS, we recommend using an upper limit goal for plateau pressures of 30 cm H2O, over higher plateau pressures. Strong , moderate-quality evidence 51. For adults with moderate to severe sepsis-induced ARDS, we suggest using higher PEEP over lower PEEP. Weak , moderate-quality evidence 52. For adults with sepsis-induced respiratory failure (without ARDS), we suggest using low tidal volume as compared with high tidal volume ventilation. Weak , low quality of evidence 53. For adults with sepsis-induced moderate-severe ARDS, we suggest using traditional recruitment maneuvers. Weak , moderate-quality evidence 54. When using recruitment maneuvers, we recommend against using incremental PEEP titration/strategy. Strong , moderate-quality evidence 55. For adults with sepsis-induced moderate-severe ARDS, we recommend using prone ventilation for greater than 12 hr daily. Strong , moderate-quality evidence 56. For adults with sepsis induced moderate-severe ARDS, we suggest using intermittent NMBA boluses, over NMBA continuous infusion. Weak , moderate-quality evidence 57. For adults with sepsis-induced severe ARDS, we suggest using Veno-venous (VV) ECMO when conventional mechanical ventilation fails in experienced centers with the infrastructure in place to support its use. Weak , low quality of evidence NEW ADDITIONAL THERAPIES 58. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IV corticosteroids. Weak , moderate-quality evidence UPGRADE from Weak recommendation , low quality of evidence "We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg/day." 59. For adults with sepsis or septic shock we suggest against using polymyxin B hemoperfusion. Weak , low quality of evidence NEW from previous: "We make no recommendation regarding the use of blood purification techniques" 60. There is insufficient evidence to make a recommendation on the use of other blood purification techniques. No recommendation 61. For adults with sepsis or septic shock we recommend using a restrictive (over liberal) transfusion strategy. Strong , moderate-quality evidence 62. For adults with sepsis or septic shock we suggest against using IV immunoglobulins. Weak , low quality of evidence 63. For adults with sepsis or septic shock, and who have risk factors for gastrointestinal (GI) bleeding, we suggest using stress ulcer prophylaxis. Weak , moderate-quality evidence 64. For adults with sepsis or septic shock, we recommend using pharmacologic venous thromboembolism (VTE) prophylaxis unless a contraindication to such therapy exists. Strong , moderate-quality evidence 65. For adults with sepsis or septic shock, we recommend using low molecular weight heparin over unfractionated heparin for VTE prophylaxis Strong , moderate-quality evidence 66. For adults with sepsis or septic shock, we suggest against using mechanical VTE prophylaxis, in addition to pharmacological prophylaxis, over pharmacologic prophylaxis alone. Weak , low quality of evidence 67. In adults with sepsis or septic shock and AKI, we suggest using either continuous or intermittent renal replacement therapy. Weak , low quality of evidence 68. In adults with sepsis or septic shock and AKI, with no definitive indications for renal replacement therapy, we suggest against using renal replacement therapy. Weak , moderate-quality evidence 69. For adults with sepsis or septic shock, we recommend initiating insulin therapy at a glucose level of ≥ 180mg/dL (10 mmol/L). Strong , moderate-quality evidence 70. For adults with sepsis or septic shock we suggest against using IV vitamin C. Weak , low quality of evidence NEW 71. For adults with septic shock and hypoperfusion-induced lactic acidemia, we suggest against using sodium bicarbonate therapy to improve hemodynamics or to reduce vasopressor requirements. Weak , low quality of evidence 72. For adults with septic shock and severe metabolic acidemia (pH ≤ 7.2) and acute kidney injury (AKIN score 2 or 3), we suggest using sodium bicarbonate therapy Weak , low quality of evidence 73. For adult patients with sepsis or septic shock who can be fed enterally, we suggest early (within 72 hr) initiation of enteral nutrition. Weak , very low quality of evidence LONG-TERM OUTCOMES AND GOALS OF CARE 74. For adults with sepsis or septic shock, we recommend discussing goals of care and prognosis with patients and families over no such discussion. Best practice statement 75. For adults with sepsis or septic shock, we suggest addressing goals of care early (within 72 hr) over late (72 hr or later). Weak , low quality of evidence 76. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on any specific standardized criterion to trigger goals of care discussion. No recommendation 77. For adults with sepsis or septic shock, we recommend that the principles of palliative care (which may include palliative care consultation based on clinician judgement) be integrated into the treatment plan, when appropriate, to address patient and family symptoms and suffering. Best practice statement 78. For adults with sepsis or septic shock, we suggest against routine formal palliative care consultation for all patients over palliative care consultation based on clinician judgement. Weak , low quality of evidence 79. For adult survivors of sepsis or septic shock and their families, we suggest referral to peer support groups over no such referral. Weak , very low quality of evidence 80. For adults with sepsis or septic shock, we suggest using a handoff process of critically important information at transitions of care over no such handoff process. Weak , very low quality of evidence 81. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation on the use of any specific structured handoff tool over usual handoff processes. No recommendation 82. For adults with sepsis or septic shock and their families, we recommend screening for economic and social support (including housing, nutritional, financial, and spiritual support), and make referrals where available to meet these needs. Best practice statement 83. For adults with sepsis or septic shock and their families, we suggest offering written and verbal sepsis education (diagnosis, treatment, and post-ICU/post-sepsis syndrome) prior to hospital discharge and in the follow-up setting. Weak , very low quality of evidence 84. For adults with sepsis or septic shock and their families, we recommend the clinical team provide the opportunity to participate in shared decision making in post-ICU and hospital discharge planning to ensure discharge plans are acceptable and feasible. Best practice statement 85. For adults with sepsis and septic shock and their families, we suggest using a critical care transition program, compared with usual care, upon transfer to the floor. Weak , very low quality of evidence 86. For adults with sepsis and septic shock, we recommend reconciling medications at both ICU and hospital discharge. Best practice statement 87. For adult survivors of sepsis and septic shock and their families, we recommend including information about the ICU stay, sepsis and related diagnoses, treatments, and common impairments after sepsis in the written and verbal hospital discharge summary. Best practice statement 88. For adults with sepsis or septic shock who developed new impairments, we recommend hospital discharge plans include follow-up with clinicians able to support and manage new and long-term sequelae. Best practice statement 89. For adults with sepsis or septic shock and their families, there is insufficient evidence to make a recommendation on early post-hospital discharge follow-up compared with routine post-hospital discharge follow-up. No recommendation 90. For adults with sepsis or septic shock, there is insufficient evidence to make a recommendation for or against early cognitive therapy. No recommendation 91. For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge. Best practice statement 92. For adult survivors of sepsis or septic shock, we suggest referral to a post-critical illness follow-up program if available. Weak , very low quality of evidence 93. For adult survivors of sepsis or septic shock receiving mechanical ventilation for > 48hr or an ICU stay of > 72 hr, we suggest referral to a post-hospital rehabilitation program. Weak , very low quality of evidence (References 5–24 are referred to in the Methodology section which can be accessed at Supplemental Digital Content: Methodology.) SCREENING AND EARLY TREATMENT Screening for Patients With Sepsis and Septic Shock - 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 recommendation, moderate quality of evidence for screening. Strong recommendation, very low-quality evidence for standard operating procedures. Rationale Sepsis performance improvement programs generally consist of sepsis screening, education, measurement of sepsis bundle performance, patient outcomes, and actions for identified opportunities (25,26). Despite some inconsistency, a meta-analysis of 50 observational studies on the effect of performance improvement programs showed that these programs were associated with better adherence to sepsis bundles along with a reduction in mortality (OR, 0.66; 95% CI, 0.61–0.72) in patients with sepsis and septic shock (27). The specific components of performance improvement did not appear to be as important as the presence of a program that included sepsis screening and metrics. Sepsis screening tools are designed to promote early identification of sepsis and consist of manual methods or automated use of the electronic health record (EHR). There is wide variation in diagnostic accuracy of these tools with most having poor predictive values, although the use of some was associated with improvements in care processes (28–31). A variety of clinical variables and tools are used for sepsis screening, such as systemic inflammatory response syndrome (SIRS) criteria, vital signs, signs of infection, quick Sequential Organ Failure Score (qSOFA) or Sequential Organ Failure Assessment (SOFA) criteria, National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS) (26,32). Machine learning may improve performance of screening tools, and in a meta-analysis of 42,623 patients from seven studies for predicting hospital acquired sepsis the pooled area under the receiving operating curve (SAUROC) (0.89; 95% CI, 0.86−0.92); sensitivity (81%; 95% CI, 80−81), and specificity (72%; 95% CI, 72−72) was higher for machine learning than the SAUROC for traditional screening tools such as SIRS (0.70), MEWS (0.50), and SOFA (0.78) (32). Screening tools may target patients in various locations, such as in-patient wards, emergency departments, or ICUs (28–30,32). A pooled analysis of three RCTs did not demonstrate a mortality benefit of active screening (RR, 0.90; 95% CI, 0.51−1.58) (33–35). However, while there is wide variation in sensitivity and specificity of sepsis screening tools, they are an important component of identifying sepsis early for timely intervention. Standard operating procedures are a set of practices that specify a preferred response to specific clinical circumstances Sepsis standard operating as Early have to which a standard with components of the sepsis early and A large the between of sepsis and A of sepsis to hospitals in the in a mortality and after of sepsis with a control from other In this time mortality was lower in hospitals with higher with the sepsis bundles may a A meta-analysis of two RCTs in higher mortality (RR, 95% CI, with standard operating procedures compared with usual care, while it was in one observational 95% CI, - Recommendation 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a screening tool for sepsis or septic shock. Strong recommendation, moderate-quality evidence. Rationale The qSOFA three variables to and prolonged ICU stay in patients with or suspected a Score a respiratory ≥ and a blood pressure ≤ mm When any two of these variables are the patient is qSOFA analysis used to support the recommendations of the on the of Sepsis identified qSOFA as a of poor in patients with or suspected infection, but no analysis was to support its use as a screening tool that time studies have the use of the qSOFA as a screening tool for sepsis The have been as to its have that qSOFA is more specific but than having two of SIRS for early identification of infection induced organ dysfunction SIRS qSOFA are screening tools for sepsis and the clinician to the of In the that of patients a qSOFA score 2 or but these patients for of poor have been when against the National Early Score and the Modified Early Score (MEWS) the presence of a qSOFA should the clinician to the of sepsis in all given the poor sensitivity of the the a strong recommendation against its use as a screening -

Abstract The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively 1–3 . In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function 4 . Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.

Adaptation is a general property of sensory receptor neurons and has been extensively studied in isolated cell preparation of olfactory receptor neurons. In contrast, little is known about the conditions under which peripheral adaptation occurs in the CNS during odorant stimulation. Here, we used two-photon laser-scanning microscopy and targeted extracellular recording in freely breathing anesthetized rats to investigate the correlate of peripheral adaptation at the first synapse of the olfactory pathway in olfactory bulb glomeruli. We find that during sustained stimulation at high concentration, odorants can evoke local field potential (LFP) postsynaptic responses that rapidly adapt with time, some within two inhalations. Simultaneous measurements of LFP and calcium influx at olfactory receptor neuron terminals reveal that postsynaptic adaptation is associated with a decrease in odorant-evoked calcium response, suggesting that it results from a decrease in glutamate release. This glomerular adaptation was concentration-dependent and did not change the glomerular input–output curve. In addition, <i>in situ</i> application of antagonists of either ionotropic glutamate receptors or metabotropic GABA_B receptors did not affect this adaptation, thus discarding the involvement of local presynaptic inhibition. Glomerular adaptation, therefore, reflects the response decline of olfactory receptor neurons to sustained odorant. We postulate that peripheral fast adaptation is a means by which glomerular output codes for high concentration of odor.

BACKGROUND: Uncontrolled bleeding is a leading cause of death in trauma. Two randomized, placebo-controlled, double-blind trials (one in blunt trauma and one in penetrating trauma) were conducted simultaneously to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma. METHODS: Severely bleeding trauma patients were randomized to rFVIIa (200, 100, and 100 microg/kg) or placebo in addition to standard treatment. The first dose followed transfusion of the eighth red blood cell (RBC) unit, with additional doses 1 and 3 hours later. The primary endpoint for bleeding control in patients alive at 48 hours was units of RBCs transfused within 48 hours of the first dose. RESULTS: Among 301 patients randomized, 143 blunt trauma patients and 134 penetrating trauma patients were eligible for analysis. In blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (estimated reduction of 2.6 RBC units, p = 0.02), and the need for massive transfusion (>20 units of RBCs) was reduced (14% vs. 33% of patients; p = 0.03). In penetrating trauma, similar analyses showed trends toward rFVIIa reducing RBC transfusion (estimated reduction of 1.0 RBC units, p = 0.10) and massive transfusion (7% vs. 19%; p = 0.08). Trends toward a reduction in mortality and critical complications were observed. Adverse events including thromboembolic events were evenly distributed between treatment groups. CONCLUSION: Recombinant FVIIa resulted in a significant reduction in RBC transfusion in severe blunt trauma. Similar trends were observed in penetrating trauma. The safety of rFVIIa was established in these trauma populations within the investigated dose range.

Three lineages (BA.1, BA.2 and BA.3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern predominantly drove South Africa's fourth Coronavirus Disease 2019 (COVID-19) wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and similar to BA.2 except for the addition of 69-70 deletion (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild-type amino acid at Q493. The two lineages differ only outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimated growth advantages for BA.4 and BA.5 of 0.08 (95% confidence interval (CI): 0.08-0.09) and 0.10 (95% CI: 0.09-0.11) per day, respectively, over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.

The recently emerged novel coronavirus, "severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)", caused a highly contagious disease called coronavirus disease 2019 (COVID-19). The virus was first reported from Wuhan city in China in December, 2019, which in less than three months spread throughout the globe and was declared a global pandemic by the World Health Organization (WHO) on 11th of March, 2020. So far, the ongoing pandemic severely damaged the world's most developed countries and is becoming a major threat for low- and middle-income countries. The poorest continent, Africa with the most vulnerable populations to infectious diseases, is predicted to be significantly affected by the ongoing COVID-19 outbreak. Therefore, in this review we collected and summarized the currently available literature on the epidemiology, etiology, vulnerability, preparedness and economic impact of COVID-19 in Africa, which could be useful and provide necessary information on ongoing COVID-19 pandemics in the continent. We also briefly summarized the concomitance of the COVID-19 pandemic and global warming.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

The Surviving Sepsis Campaign (SSC) International Guidelines for the Management of Sepsis and Septic Shock provide guidance on the care of hospitalized adult patients with (or at risk for) sepsis, based on systematic summary and assessment of relevant literature. This executive summary reviews the history, scope, methodology, and major recommendations of the guidelines, focusing on aspects that are new or different compared with the 2016 guidelines that were published in 2017. Full description of the guidelines process and recommendations are provided in the complete guidelines document. HISTORY AND SCOPE OF THE GUIDELINES The SSC first published guidelines for the management of severe sepsis and septic shock in 2004. Updates were published in 2008, 2012, and 2017. The guidelines are sponsored by the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM), with methodological support by the Guidelines in Intensive Care Development and Evaluation (GUIDE) group, and endorsement by 24 additional societies. There is no funding from any industry partner. Panel membership, patient involvement, and conflict of interest management are discussed in the complete guidelines document. The guidelines provide recommendations on the management of sepsis, focusing on aspects of care specific to sepsis and limiting duplication with other guidelines wherever possible. It is not intended to replace clinical judgement, which must account for the unique circumstances of an individual patient. Following the recommendation of SCCM and ESICM, there are now separate guidelines for sepsis in children (1). The SSC also published separate guidelines specific to the management of COVID (2,3). The 2021 guidelines largely apply to high-resource settings but discuss applicability of the recommendations to lower-resource settings as data allow. The SSC also creates sepsis bundles (4) (a selected set of interventions or processes of care distilled from evidence-based practice guidelines) to facilitate quality improvement and implementation of guidelines recommendations. However, the bundles are developed via a separate process and published separately from the guidelines. Definitions The guidelines recognize sepsis as life-threatening organ dysfunction secondary to a dysregulated host response to infection consistent with the Sepsis-3 consensus definition (5). However, studies were not required to use a particular sepsis definition to be considered as relevant evidence for the guidelines. Question Development and Outcome Prioritization Guidelines questions were selected based on panel rating, clinical practice variability, and inclusion in prior SSC guidelines, and then assigned to one of six SSC adult guidelines working groups: screening and initial resuscitation; infection; hemodynamics; ventilation; additional therapies; and goals of care and long-term outcomes. Clinical practice variation was identified through a global survey of SCCM and ESICM members regarding their current practice and how it related to previous recommendations. All questions were structured in the Population, Intervention, Control, and Outcomes (PICO) format. For each question, relevant outcomes were enumerated and ranked prior to the literature search. Search Strategy and Evidence Summation Professional librarians drafted and executed the search strategy for each PICO question (or group of similar questions), with input from subgroup members. Only English language studies published before May 2019 were included (the lag was the result of the guideline review and approval process coupled with the COVID-19 pandemic). For PICO questions addressed in the 2016 guidelines, the search strategy was revised and updated. Reviewers in the systematic review team, with input from methodologists and experts, screened article titles and abstracts to identify the highest quality evidence, particularly recent randomized controlled trials and high-quality systematic reviews. When new or updated meta-analyses were required, relevant data were abstracted with emphasis on intention-to-treat data where possible and conventional meta-analytic techniques were used to produce pooled estimates. Quality of Evidence and Formulation of Recommendations Using the GRADE approach, methodologists and panelists assessed the quality of evidence for each PICO question as high, moderate, low, or very low. Using the Evidence-to-Decision (EtD) framework (6), each subgroup drafted preliminary recommendations for their assigned PICO questions. The EtD framework took into account not only the magnitude of effect and quality of evidence, but also patient values, resources and cost, equity, acceptability, and feasibility (6). The strength of each recommendation was informed by the quality of the evidence and other components of the EtD framework. Strong recommendations (signified by “we recommend”) reflect high confidence that the desirable effects of adhering to a recommendation clearly outweigh undesirable effects. Weak recommendations (signified by “we suggest”) indicate that desirable effects likely outweigh undesirable effects. Best practice statements (BPSs) reflect ungraded strong recommendations and are used sparingly when benefit or harm is unequivocal, but evidence is difficult to summarize or assess according to GRADE methodology (7). Voting Progress Preliminary recommendations were discussed during face-to-face meetings and revised based on panel feedback prior to electronic voting by panel members who had no conflicts of interest. The a priori threshold for acceptance was having votes cast by at least 75% of the panel and 80% agreement among those who cast a vote. Up to three rounds of voting were allowed per PICO question. RECOMMENDATIONS The recommendations of the SSC 2021 guidelines update are summarized in Table 1 of the full guidelines document. There are 93 total statements, which address screening and initial resuscitation (n = 10 statements), infection (n = 21), hemodynamics (n = 14), ventilation (n = 12), additional therapies (n = 16), and goals of care and long-term outcomes (n = 20). Of the 93 statements, 15 are strong (16%) and 54 are weak (58%) recommendations, 15 are best practice statements (16%), and 9 are statements declaring ‘no recommendation’ (10%). Of the 15 strong recommendations, all but one are based on moderate or high-quality evidence. Selected recommendations that are new or revised from the 2016 guidelines are shown in Table 1. TABLE 1. - Selected New and/or Revised Recommendations in the 2021 Surviving Sepsis Campaign International Guidelines for the Management of Sepsis and Septic Shock 2016 Recommendation 2021 Recommendation Rationale for Change We recommend that in the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hours. 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. This panel downgraded this recommendation from a strong recommendation to a weak recommendation based on the low quality of the evidence. There are no prospective intervention studies comparing different volumes for initial resuscitation in sepsis or septic shock. However, a retrospective analysis of adults presenting to an emergency department with sepsis or septic shock showed that failure to receive 30mL/kg of crystalloid fluid therapy within 3 hours of sepsis onset was associated with higher in-hospital mortality (10). Furthermore, the average volume of fluid received pre-randomization the PROCESS (11), PROMISE (12), and ARISE (13) trials was in the range of 30 mL/kg, suggesting this fluid volume has been adopted in routine clinical practice (14). We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock. For adults with sepsis or septic shock, we suggest using balanced crystalloid instead of normal saline for resuscitation. There are many, increasingly recognized potential adverse effects of normal saline including hyperchloremic metabolic acidosis. A network meta-analysis showed in an indirect comparison that balanced fluids were associated with decreased mortality compared with saline (15). In the 2018 SMART single-center cluster-randomized RCT comparing saline to balance fluid, the pre-specified subgroup of patients admitted with sepsis experienced lower 30-day mortality when randomized to balanced fluids versus saline (OR, 0.90; 95% CI, 0.67, 0.94) (16). Not addressed For adults with septic shock, we suggest starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until a central venous access is secured. Prompt initiation of vasopressors is an integral component of septic shock management. Vasopressors have been traditionally administered via central venous access due to concerns of extravasation and local tissue injury and ischemia. However, placement of central venous access requires specialized expertise and is time consuming, potentially leading to delays in administration. A recent systematic review showed that peripheral administration of vasopressors is generally safe, particularly if infused distally to the antecubital fossa and for short periods of time (< 6 hr) (17, 18). Peripheral administration of vasopressors is associated with shorter time to administration and faster time to achieving a MAP > 65 mm Hg (19). Not addressed For adults with sepsis or septic shock we suggest against using IV vitamin C. A 2017 single center before and after study reported reduced mortality with administration of high-dose Vitamin C, hydrocortisone, and thiamine among patients with sepsis and sepsis shock (20). However, an updated meta-analysis by the guideline panel found no association between vitamin C and reduced mortality. We suggest against using IV hydrocortisone to treat patients with septic shock if adequate fluid resuscitation and vasopressor therapy can restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg/day. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IVcorticosteroids. Since the 2016 guideline, three large RCTs have been published (21–23). An updated meta-analysis found systemic corticosteroid to accelerate resolution of shock (MD, 1.52 days; 95% CI, 1.71 to 1.32) and increase vasopressor-free days (MD, 1.5 days; 95% CI, 0.8 to 3.11 days) (24). However, corticosteroid use increased neuromuscular weakness (RR, 1.21; 95% CI, 1.01 to 1.45), without a clear effect on short- or long-term mortality (24). The overall quality of evidence was moderate. The panel judged the desirable effects (shock resolution, vasopressor-free days) to outweigh the undesirable effects. This observation, combined with consideration of the resources required, cost of the intervention, and feasibility supported a weak recommendation in favor of using low-dose corticosteroid therapy in septic shock. Not addressed For adult survivors of sepsis or septic shock, we recommend assessment and follow-up for physical, cognitive, and emotional problems after hospital discharge. Given the prevalence of new and worsening physical, cognitive, and emotional problems experienced by sepsis survivors, we recommend assessment and follow-up of these problems after discharge. Screening and Initial Resuscitation The guidelines recommend that hospitals use a performance improvement program for sepsis, including screening of high-risk patients and standard operating procedures for management. The guidelines recognize sepsis as a medical emergency and recommend that treatment and resuscitation begin immediately. For initial resuscitation in patients with sepsis-induced hypoperfusion or septic shock, the guidelines suggest 30 mL/kg IV crystalloid. This recommendation was downgraded from a strong recommendation to a weak recommendation based on the low quality of evidence. Additionally, the guidelines suggest resuscitation be guided by dynamic over static measures, target a decrease in serum lactate, and use capillary refill as an adjunct measure of perfusion. New to this update, the guidelines recommend against qSOFA as a sole screening tool and suggest that patients who are determined to need intensive care be admitted to an ICU within 6 hours. Infection As in the 2016 guidelines, the 2021 guidelines again recommend delivering antimicrobials as soon as possible, ideally within 1 hour of sepsis recognition. The 2021 guidelines provide additional guidance on initiation of antimicrobials, recognizing the challenge of diagnostic uncertainty early in a patient’s presentation. The guidelines now stratify antimicrobial timing recommendations based on the likelihood of sepsis and presence of shock (Figure 1). For patients with probable sepsis or with shock resulting from possible or probable sepsis, the guidelines recommend administering antimicrobials immediately, ideally within 1 hour of recognition. For patients with possible sepsis but without shock, the guidelines recommend rapid assessment of the likelihood of infection versus non-infectious illness. If concern for infection persists after a time-limited course of rapid investigation, then antimicrobials should be administered within 3 hours from when sepsis was first recognized. Finally, for patients with a low likelihood of infection and without shock, the guidelines suggest deferring antimicrobials while continuing to closely monitor the patient.Figure 1.: 2021 Recommendations of the initiation of antimicrobials.The guidelines include several additional recommendations regarding antimicrobial therapy for sepsis. Given the heterogeneity of infectious pathogens, sites of infection, severity of illness, local resistance patterns, and other patient and contextual factors, specific treatment recommendations are beyond the scope of the guidelines. However, the guidelines provide a framework for approaching antimicrobial therapy. They suggest that use of empiric coverage for methicillin-resistant Staphylococcus aureus (MRSA), empiric double-coverage for gram-negative pathogens, and empiric coverage for fungal pathogens be determined based on patient and contextual risk factors. The guidelines provide several recommendations for optimizing antibiotic dosing, addressing source control, and determining duration of antimicrobial therapy. Hemodynamics The guidelines recommend crystalloid fluids as a first line for resuscitation, and new in this update, suggest balanced crystalloids over normal saline. For patients with septic shock, the guidelines recommend norepinephrine as the first-line vasopressor and suggest that vasopressors be started peripherally to avoid delays in administration in the absence of central venous access. There was insufficient evidence to make a recommendation regarding the use of a restrictive versus liberal fluid strategy after the initial fluid resuscitation, and this remains an important area for future research. As in the 2016 guidelines, albumin is suggested in patients who have received large volumes of crystalloid. Ventilation The guidelines recommend a low tidal volume ventilation strategy with limitation of plateau pressure for patients with sepsis-associated ARDS and the use of prone positioning in moderate-to-severe ARDS, and suggest a low tidal volume approach for all patients with sepsis-induced respiratory failure. The guidelines suggest using traditional recruitment maneuvers but recommend against an incremental PEEP strategy. There was insufficient evidence to make a recommendation regarding use of liberal versus conservative oxygen targets; this remains an important area for future research. Additional Therapies To limit overlap with other guidelines and create space for a new section focused on long-term outcomes, PICOs on additional therapies were reduced from prior SSC guidelines. However, there are some noteworthy new recommendations regarding adjunctive therapies. In contrast to the 2016 guidelines, the 2021 guidelines suggest the use of IV corticosteroids for patients with an ongoing need for vasopressor therapy based on newer clinical trial data. Additionally, the guidelines suggest against using IV vitamin C for sepsis or septic shock based on recent randomized controlled trials and an updated meta-analysis showing no impact on mortality. Goals of Care and Long-Term Outcomes As acute survival from sepsis has improved, a growing number of sepsis survivors leave the hospital alive—many of whom experience long-term morbidity and a heightened risk for adverse health outcomes including mortality in the months and years following sepsis (8). Indeed, the 2017 World Health Organization resolution on sepsis called for improving outcomes of sepsis survivors and addressing survivors’ access to rehabilitation (9). Given the burden of long-term morbidity and mortality stemming from sepsis, the SSC guidelines now include a section dedicated to the longer-term recovery from sepsis. To enhance recovery, the guidelines recommend screening for economic and social support for patient and families, involving patients and families in shared decision-making regarding discharge planning, reconciling medications at both ICU and hospital discharge, including information about sepsis and common impairment after sepsis in the discharge summary, and assessing for physical, cognitive, and emotional problems after hospital discharge. The guidelines suggest having a critical care transitional program during ICU stay to floor transitions, using a handoff process during transitions of care, offering verbal and written sepsis education, and referring patients to peer support programs, post-critical illness follow-up programs (if available), and post-hospital rehabilitation programs (for selected survivors). There was insufficient evidence to make a recommendation regarding early cognitive rehabilitation or timing of post-hospital follow up. While many of these recommendations are generally applicable to critically ill and hospitalized patients, the panel deemed them necessary to include in the sepsis guidelines given the burden of long-term morbidity and mortality due to sepsis. CONCLUSIONS This executive summary highlights the most novel aspects of the Surviving Sepsis Campaign International Guidelines for the Management of Sepsis and Septic Shock 2021 that clinicians and stakeholders should consider when caring for adult patients with (or at risk for) sepsis. The recommendation rationales, informed by rigorous data evaluation, discussion by panelists, and input from patients, provide deeper insight into each recommendation. We believe that the 2021 SSC guidelines will foster the delivery of best practices for sepsis evaluation and management, as well as highlight aspects of management where additional evidence is needed most urgently.

We performed a prospective, international, observational study of 844 hospitalized patients with blood cultures positive for Streptococcus pneumoniae. Fifteen percent of isolates had in vitro intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC], 0.12-1 microg/mL), and 9.6% of isolates were resistant (MIC, >or=2 microg/mL). Age, severity of illness, and underlying disease with immunosuppression were significantly associated with mortality; penicillin resistance was not a risk factor for mortality. The impact of concordant antibiotic therapy (i.e., receipt of a single antibiotic with in vitro activity against S. pneumoniae) versus discordant therapy (inactive in vitro) on mortality was assessed at 14 days. Discordant therapy with penicillins, cefotaxime, and ceftriaxone (but not cefuroxime) did not result in a higher mortality rate. Similarly, time required for defervescence and frequency of suppurative complications were not associated with concordance of beta-lactam antibiotic therapy. beta-Lactam antibiotics should still be useful for treatment of pneumococcal infections that do not involve cerebrospinal fluid, regardless of in vitro susceptibility, as determined by current NCCLS breakpoints.

There is a need for a clear definition of exacerbations used in clinical trials in patients with bronchiectasis. An expert conference was convened to develop a consensus definition of an exacerbation for use in clinical research.A systematic review of exacerbation definitions used in clinical trials from January 2000 until December 2015 and involving adults with bronchiectasis was conducted. A Delphi process followed by a round-table meeting involving bronchiectasis experts was organised to reach a consensus definition. These experts came from Europe (representing the European Multicentre Bronchiectasis Research Collaboration), North America (representing the US Bronchiectasis Research Registry/COPD Foundation), Australasia and South Africa.The definition was unanimously approved by the working group as: a person with bronchiectasis with a deterioration in three or more of the following key symptoms for at least 48 h: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; haemoptysis AND a clinician determines that a change in bronchiectasis treatment is required.The working group proposes the use of this consensus-based definition for bronchiectasis exacerbation in future clinical research involving adults with bronchiectasis.

Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in hemophilia A. Emicizumab prophylaxis in children with hemophilia A and FVIII inhibitors was investigated in a phase 3 trial (HAVEN 2). Participants, previously receiving episodic/prophylactic bypassing agents (BPAs), were treated with subcutaneous emicizumab: 1.5 mg/kg weekly (group A), 3 mg/kg every 2 weeks (group B), or 6 mg/kg every 4 weeks (group C). Pharmacokinetics, safety, and efficacy (including an intraindividual comparison of participants from a noninterventional study) were evaluated. Eighty-five participants aged <12 years were enrolled. In group A (n = 65), the annualized rate of treated bleeding events (ABRs) was 0.3 (95% confidence interval [CI], 0.17-0.50), and 77% had no treated bleeding events. Intraindividual comparison of 15 participants who previously took BPA prophylaxis showed that emicizumab prophylaxis reduced the ABR by 99% (95% CI, 97.4-99.4). In groups B (n = 10) and C (n = 10), ABRs were 0.2 (95% CI, 0.03-1.72) and 2.2 (95% CI, 0.69-6.81), respectively. The most frequent adverse events were nasopharyngitis and injection-site reactions; no thrombotic events occurred. Two of 88 participants developed antidrug antibodies (ADAs) with neutralizing potential, that is, associated with decreased emicizumab plasma concentrations: 1 experienced loss of efficacy, and, in the other, ADAs disappeared over time without intervention or breakthrough bleeding. All other participants achieved effective emicizumab plasma concentrations, regardless of the treatment regimen. Emicizumab prophylaxis has been shown to be a highly effective novel medication for children with hemophilia A and inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT02795767.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

BACKGROUND: Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. METHODS: We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. RESULTS: As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. CONCLUSIONS: Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).

The first recognised outbreak of Marburg virus disease in Africa, and the first since the original epidemic in West Germany and Yugoslavia in 1967, occurred in South Africa in February 1975. The primary case was in a young Australian man , who was admitted to the Johannesburg Hospital after having toured Rhodesia. Two secondary cases occurred, one being in the first patient's travelling companion, and the other in a nurse. Features of the illness included high fever, myalgia, vomiting and diarrhoea, hepatitis, a characteristic maculopapular rash, leucopenia, thrombocytopenia, and a bleeding tendency. The first patient died on the seventh day from haemorrhage resulting from a combination of disseminated intravascular coagulation and hepatic failure. The other two patients were given vigorous supportive treatment and prophylactic heparin and recovered after an acute phase lasting about seven days. During this period on developed pancreatitis, the serum amylase remaining raised until the 32nd day after the onset of the illness. The other developed unilateral uveitis after having been asymptomatic for two months. This persisted for several weeks and Marburg virus was cultured from the anterior chamber of the eye.

SUMMARY The clinical and neurodevelopmental features are presented of four children–two sibling pairs–who were exposed in utero to valproic acid. One of each pair of children presented for diagnosis and assessment of developmental delay; the other sibling was examined at a later date. Three of the children were globally developmentally delayed with marked speech disability, and had dysmorphic features consistent with fetal valproate syndrome. One also had features of infantile autism. The fourth child had some of the dysmorphic features connected with fetal valproate syndrome, but had normal intellect, with his verbal ability being significantly below his non‐verbal ability. He currently attends a school for learning‐disabled children. RÉSUMÉ Le syndrome foetal du valproate: données cliniques et neuro‐développementales dans deux paires de méme fratrie Les données cliniques et neuro‐développementales de quatrc enfants, deux paires de même fratrie, exposés in utero á l'acide valproïque, sont présentées. Dans chaque paire, un enfant fut examiné initialement pour le diagnostic et l'évaluation d'un retard de développement; l'autre membre de la fratrie étant examiné ultérieurement. Chez trois des enfants, il fut noté un trouble net du langage, des caractéres dysmorphiques en rapport avec le syndrome foetal du valproate. Un enfant présentait en outre le tableau d'un autisme infantile. Le quatriéme enfant présentait quelques éléments dysmorphiques caractéristiques du syndrome foetal de valproate mais son intelligence était normale, bien que ses capacités verbales aient été manifestement inférieures á ses capacités non verbales. II fréquente actuellement une école pour enfants en difficultés d'apprentissage. ZUSAMMENFASSUNG Valproai‐Embryofelopathie: klinische und entwieklungsneurologische Merkmale bei zwei Zwillingspaaren Es werden die klinischen und entwicklungsneurologischen Merkmale bei vier Kindern—zwei Zwillingspaaren beschrieben, die in utero eine Exposition zu Valproinsaura hatten. Je ein Zwillingskind wurde wegen einer Entwicklungsverzögerung vorgestellt und untersucht, die beiden anderen Kinder wurden zu einem spateren Zeitpunkt untersucht. Drei der Kinder hatten eine globale Entwicklungsverzogerung mit ausgeprägten Sprachschwierigkeiten und Dysmorphiezeichen, die für die Valproat‐Embryofetopathie typisch sind. Ein Kind hatte außerdem Symptome eines infantilen Autismus. Das vierte Kind hatte einige der typischen Dysmorphiezeichen, aber es hatte einen normalen Intellekt, wobei seine verbalen Fähigkeiten signifikant schlechter waren als seine non‐verbalen. Zur Zeit besucht es eine Schule für lernbehinderte Kinder. RESUMEN Sindrome fetal del valproate: caracteristicas clinicas y neuroevolutivas en dos pares de hermanos Se presentan las caracteristicas clinicas y neuroevolutivas de cuatro niños (dos pares de hermanos) que habian sido expuestos in utero a ácido valproico. Uno de cada pareja de hermanos acudieron a la consulta para diagnóstico y evaluatión de un retraso en el desarrollo; el otro hermano fue examinado un tiempo más tarde. Tres de los niños tenían un retraso global del desarrollo con una marcada dificultad en el lenguaje y tenian caracteristicas dismórficas del tipo del sindrome fetal del valproate. Uno de los niños tenia también signos de autismo infantil. El cuarto niño tenia algunos de los signos dismórficos en relación con el sindrome del valproato pero tenia un intclecto normal y su habilidad verbal era significativamente menor que su habilidad no verbal; acude habitualmente a una escuela especial para niños discapacitados.

Echinococcosis or hydatid disease is caused by larvae of the tapeworm Echinococcus. Four species are recognised and the vast majority of infestations in humans are caused by E. granulosus. E. granulosus causes cystic echinococcosis, which has a worldwide distribution. Humans are exposed less frequently to E. multilocularis, which causes alveolar echinococcosis. E. vogeli and E. oligarthrus are rare species and cause polycystic echinococcosis. In cystic echinococcosis, humans are an accidental host and are usually infected by handling an infected dog. The liver and lungs are the most frequently involved organs. Pulmonary disease appears to be more common in younger individuals. Although most patients are asymptomatic, some may occasionally expectorate the contents of the cyst or develop symptoms related to compression of the surrounding structures. Other symptoms of hydatid disease can result from the release of antigenic material and secondary immunological reactions that develop from cyst rupture. The cysts are characteristically seen as solitary or multiple circumscribed or oval masses on imaging. Detection of antibody directed against specific echinococcal antigens is found in only approximately half of patients with pulmonary cysts. Surgical excision of the cyst is the treatment of choice whenever feasible.

The already inadequate health systems of Africa, especially sub-Saharan Africa, have been badly damaged by the migration of their health professionals. There are 57 countries with a critical shortage of healthcare workers, a deficit of 2.4 million doctors and nurses. Africa has 2.3 healthcare workers per 1000 population, compared with the Americas, which have 24.8 healthcare workers per 1000 population. Only 1.3% of the world's health workers care for people who experience 25% of the global disease burden. The consequences for some countries resulting from loss of health workers are increasingly recognized and are now being widely aired in the public media. The health services of a continent already facing daunting challenges to the delivery of minimum standards of health care are now also being potentially overwhelmed by HIV/AIDS. There is a need for concerted political will and funding support that will allow them to do what is necessary. It may well be asked why special measures should be necessary to influence the migration of health professionals rather than engineers or football players or any other category. The answer must surely be that no other category of worker is so essential to the well-being of the population of every nation.

Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high.The 2013 update of the World Society of Emergency Surgery (WSES) guidelines for the management of intra-abdominal infections contains evidence-based recommendations for management of patients with intra-abdominal infections.

The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients initiating antiretroviral therapy (ART) results from restored immunity to specific infectious or non-infectious antigens. A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating therapy characterizes the syndrome. Potential mechanisms for the syndrome include a partial recovery of the immune system or exuberant host immunological responses to antigenic stimuli. The overall incidence of IRIS is unknown, but is dependent on the population studied and its underlying opportunistic infectious burden. The infectious pathogens most frequently implicated in the syndrome are mycobacteria, varicella zoster, herpesviruses, and cytomegalovirus (CMV). No single treatment option exists and depends on the underlying infectious agent and its clinical presentation. Prospective cohort studies addressing the optimal screening and treatment of opportunistic infections in patients eligible for ART are currently being conducted. These studies will provide evidence for the development of treatment guidelines in order to reduce the burden of IRIS. We review the available literature on the pathogenesis and epidemiology of IRIS, and present treatment options for the more common infectious manifestations of this diverse syndrome and for manifestations associated with a high morbidity.

OBJECTIVE: To determine the incidence, clinical manifestations, risk factors and outcome of immune reconstitution inflammatory syndrome (IRIS) in South Africa. DESIGN: Prospective surveillance cohort and nested case-control study in a large, University hospital-based antiretroviral therapy (ART) clinic. METHODS: A total of 423 ART-naive HIV-infected South African patients were followed for signs and symptoms IRIS during the first 6 months of ART. We also performed a nested case-control study with controls matched to IRIS cases on ART duration. RESULTS: During the first 6 months of ART, 44 (10.4%) patients experienced IRIS for an overall incidence rate of 25.1 cases per 100 patient-years. Diagnoses included tuberculosis (18/44, 41%), abscess formation and suppurative folliculitis (8/44, 18.2%), varicella zoster (6/44, 13.6%), herpes simplex (4/44, 9.1%), cryptococcal meningitis (3/44, 6.8%), molluscum contagiosum (3/44, 6.8%), and Kaposi's sarcoma (2/44, 4.5%). Median IRIS onset was 48 days (interquartile range, 29-99) from ART initiation. In comparison with controls, IRIS cases had significantly lower CD4 cell counts at baseline (79 versus 142 cells/microl; P = 0.02) and at IRIS diagnosis (183 versus 263 cells/microl; P = 0.05), but similar virological and immunological response to ART. In multivariable analyses, higher baseline CD4 cell count was protective of developing IRIS (HR 0.72 per 50 cells/microl increase). Most IRIS cases were mild, with ART discontinued in three (6.8%) patients, corticosteroids administered to four (9.1%) patients, and hospitalization required in 12 (27.3%) patients. Two deaths were attributable to IRIS. CONCLUSIONS: IRIS may affect 10% of patients initiating ART in Africa, particularly those with advanced immunosuppression, but severe, life-threatening IRIS is uncommon.