Philippine General Hospital

OBJECTIVE: Traumatic brain injury (TBI)-the "silent epidemic"-contributes to worldwide death and disability more than any other traumatic insult. Yet, TBI incidence and distribution across regions and socioeconomic divides remain unknown. In an effort to promote advocacy, understanding, and targeted intervention, the authors sought to quantify the case burden of TBI across World Health Organization (WHO) regions and World Bank (WB) income groups. METHODS: Open-source epidemiological data on road traffic injuries (RTIs) were used to model the incidence of TBI using literature-derived ratios. First, a systematic review on the proportion of RTIs resulting in TBI was conducted, and a meta-analysis of study-derived proportions was performed. Next, a separate systematic review identified primary source studies describing mechanisms of injury contributing to TBI, and an additional meta-analysis yielded a proportion of TBI that is secondary to the mechanism of RTI. Then, the incidence of RTI as published by the Global Burden of Disease Study 2015 was applied to these two ratios to generate the incidence and estimated case volume of TBI for each WHO region and WB income group. RESULTS: Relevant articles and registries were identified via systematic review; study quality was higher in the high-income countries (HICs) than in the low- and middle-income countries (LMICs). Sixty-nine million (95% CI 64-74 million) individuals worldwide are estimated to sustain a TBI each year. The proportion of TBIs resulting from road traffic collisions was greatest in Africa and Southeast Asia (both 56%) and lowest in North America (25%). The incidence of RTI was similar in Southeast Asia (1.5% of the population per year) and Europe (1.2%). The overall incidence of TBI per 100,000 people was greatest in North America (1299 cases, 95% CI 650-1947) and Europe (1012 cases, 95% CI 911-1113) and least in Africa (801 cases, 95% CI 732-871) and the Eastern Mediterranean (897 cases, 95% CI 771-1023). The LMICs experience nearly 3 times more cases of TBI proportionally than HICs. CONCLUSIONS: Sixty-nine million (95% CI 64-74 million) individuals are estimated to suffer TBI from all causes each year, with the Southeast Asian and Western Pacific regions experiencing the greatest overall burden of disease. Head injury following road traffic collision is more common in LMICs, and the proportion of TBIs secondary to road traffic collision is likewise greatest in these countries. Meanwhile, the estimated incidence of TBI is highest in regions with higher-quality data, specifically in North America and Europe.

OBJECTIVES: To estimate COVID-19 infections and deaths in healthcare workers (HCWs) from a global perspective during the early phases of the pandemic. DESIGN: Systematic review. METHODS: Two parallel searches of academic bibliographic databases and grey literature were undertaken until 8 May 2020. Governments were also contacted for further information where possible. There were no restrictions on language, information sources used, publication status and types of sources of evidence. The AACODS checklist or the National Institutes of Health study quality assessment tools were used to appraise each source of evidence. OUTCOME MEASURES: Publication characteristics, country-specific data points, COVID-19-specific data, demographics of affected HCWs and public health measures employed. RESULTS: A total of 152 888 infections and 1413 deaths were reported. Infections were mainly in women (71.6%, n=14 058) and nurses (38.6%, n=10 706), but deaths were mainly in men (70.8%, n=550) and doctors (51.4%, n=525). Limited data suggested that general practitioners and mental health nurses were the highest risk specialities for deaths. There were 37.2 deaths reported per 100 infections for HCWs aged over 70 years. Europe had the highest absolute numbers of reported infections (119 628) and deaths (712), but the Eastern Mediterranean region had the highest number of reported deaths per 100 infections (5.7). CONCLUSIONS: COVID-19 infections and deaths among HCWs follow that of the general population around the world. The reasons for gender and specialty differences require further exploration, as do the low rates reported in Africa and India. Although physicians working in certain specialities may be considered high risk due to exposure to oronasal secretions, the risk to other specialities must not be underestimated. Elderly HCWs may require assigning to less risky settings such as telemedicine or administrative positions. Our pragmatic approach provides general trends, and highlights the need for universal guidelines for testing and reporting of infections in HCWs.

BACKGROUND: Probiotics may be effective in reducing the duration of acute infectious diarrhoea. OBJECTIVES: To assess the effects of probiotics in proven or presumed acute infectious diarrhoea. SEARCH METHODS: We searched the trials register of the Cochrane Infectious Diseases Group, MEDLINE, and Embase from inception to 17 December 2019, as well as the Cochrane Controlled Trials Register (Issue 12, 2019), in the Cochrane Library, and reference lists from studies and reviews. We included additional studies identified during external review. SELECTION CRITERIA: Randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent. DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria, assessed risk of bias, and extracted data. Primary outcomes were measures of diarrhoea duration (diarrhoea lasting ≥ 48 hours; duration of diarrhoea). Secondary outcomes were number of people hospitalized in community studies, duration of hospitalization in inpatient studies, diarrhoea lasting ≥ 14 days, and adverse events. MAIN RESULTS: We included 82 studies with a total of 12,127 participants. These studies included 11,526 children (age < 18 years) and 412 adults (three studies recruited 189 adults and children but did not specify numbers in each age group). No cluster-randomized trials were included. Studies varied in the definitions used for "acute diarrhoea" and "end of the diarrhoeal illness" and in the probiotic(s) tested. A total of 53 trials were undertaken in countries where both child and adult mortality was low or very low, and 26 where either child or adult mortality was high. Risk of bias was high or unclear in many studies, and there was marked statistical heterogeneity when findings for the primary outcomes were pooled in meta-analysis. Effect size was similar in the sensitivity analysis and marked heterogeneity persisted. Publication bias was demonstrated from funnel plots for the main outcomes. In our main analysis of the primary outcomes in studies at low risk for all indices of risk of bias, no difference was detected between probiotic and control groups for the risk of diarrhoea lasting ≥ 48 hours (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 2 trials, 1770 participants; moderate-certainty evidence); or for duration of diarrhoea (mean difference (MD) 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer; 6 trials, 3058 participants; very low-certainty evidence). Effect size was similar and marked heterogeneity persisted in pre-specified subgroup analyses of the primary outcomes that included all studies. These included analyses limited to the probiotics Lactobacillus rhamnosus GG and Saccharomyces boulardii. In six trials (433 participants) of Lactobacillus reuteri, there was consistency amongst findings (I² = 0%), but risk of bias was present in all included studies. Heterogeneity also was not explained by types of participants (age, nutritional/socioeconomic status captured by mortality stratum, region of the world where studies were undertaken), diarrhoea in children caused by rotavirus, exposure to antibiotics, and the few studies of children who were also treated with zinc. In addition, there were no clear differences in effect size for the primary outcomes in post hoc analyses according to decade of publication of studies and whether or not trials had been registered. For other outcomes, the duration of hospitalization in inpatient studies on average was shorter in probiotic groups than in control groups but there was marked heterogeneity between studies (I² = 96%; MD -18.03 hours, 95% CI -27.28 to -8.78, random-effects model: 24 trials, 4056 participants). No differences were detected between probiotic and control groups in the number of people with diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53; 9 studies, 2928 participants) or in risk of hospitalization in community studies (RR 1.26, 95% CI 0.84 to 1.89; 6 studies, 2283 participants). No serious adverse events were attributed to probiotics. AUTHORS' CONCLUSIONS: Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer, and we are uncertain whether probiotics reduce the duration of diarrhoea. This analysis is based on large trials with low risk of bias.

PURPOSE: Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. EXPERIMENTAL DESIGN: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS). RESULTS: Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut(+) cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14-0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut(-) cfDNA subgroup (HR, 0.83; 95% CI, 0.65-1.04, P = 0.1076). For patients with EGFR mut(+) cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut(+) cfDNA versus cycle 3 EGFR mut(-) patients, respectively (HR, 0.32; 95% CI, 0.21-0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31-0.84, P = 0.0066). CONCLUSIONS: Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes.

OBJECTIVE: Hydrocephalus is one of the most common brain disorders, yet a reliable assessment of the global burden of disease is lacking. The authors sought a reliable estimate of the prevalence and annual incidence of hydrocephalus worldwide. METHODS: The authors performed a systematic literature review and meta-analysis to estimate the incidence of congenital hydrocephalus by WHO region and World Bank income level using the MEDLINE/PubMed and Cochrane Database of Systematic Reviews databases. A global estimate of pediatric hydrocephalus was obtained by adding acquired forms of childhood hydrocephalus to the baseline congenital figures using neural tube defect (NTD) registry data and known proportions of posthemorrhagic and postinfectious cases. Adult forms of hydrocephalus were also examined qualitatively. RESULTS: Seventy-eight articles were included from the systematic review, representative of all WHO regions and each income level. The pooled incidence of congenital hydrocephalus was highest in Africa and Latin America (145 and 316 per 100,000 births, respectively) and lowest in the United States/Canada (68 per 100,000 births) (p for interaction < 0.1). The incidence was higher in low- and middle-income countries (123 per 100,000 births; 95% CI 98-152 births) than in high-income countries (79 per 100,000 births; 95% CI 68-90 births) (p for interaction < 0.01). While likely representing an underestimate, this model predicts that each year, nearly 400,000 new cases of pediatric hydrocephalus will develop worldwide. The greatest burden of disease falls on the African, Latin American, and Southeast Asian regions, accounting for three-quarters of the total volume of new cases. The high crude birth rate, greater proportion of patients with postinfectious etiology, and higher incidence of NTDs all contribute to a case volume in low- and middle-income countries that outweighs that in high-income countries by more than 20-fold. Global estimates of adult and other forms of acquired hydrocephalus are lacking. CONCLUSIONS: For the first time in a global model, the annual incidence of pediatric hydrocephalus is estimated. Low- and middle-income countries incur the greatest burden of disease, particularly those within the African and Latin American regions. Reliable incidence and burden figures for adult forms of hydrocephalus are absent in the literature and warrant specific investigation. A global effort to address hydrocephalus in regions with the greatest demand is imperative to reduce disease incidence, morbidity, mortality, and disparities of access to treatment.

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.

Since its publication in 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) have been widely adopted. The validation of TG07 conducted in terms of clinical practice has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. Discussion by the Tokyo Guidelines Revision Committee concluded that acute cholecystitis should be suspected when Murphy's sign, local inflammatory findings in the gallbladder such as right upper quadrant abdominal pain and tenderness, and fever and systemic inflammatory reaction findings detected by blood tests are present but that definite diagnosis of acute cholecystitis can be made only on the basis of the imaging of ultrasonography, computed tomography or scintigraphy (HIDA scan). These proposed diagnostic criteria provided better specificity and accuracy rates than the TG07 diagnostic criteria. As for the severity assessment criteria in TG07, there is evidence that TG07 resulted in clarification of the concept of severe acute cholecystitis. Furthermore, there is evidence that severity assessment in TG07 has led to a reduction in the mean duration of hospital stay. As for the factors used to establish a moderate grade of acute cholecystitis, such as leukocytosis, ALP, old age, diabetes, being male, and delay in admission, no new strong evidence has been detected indicating that a change in the criteria used in TG07 is needed. Therefore, it was judged that the severity assessment criteria of TG07 could be applied in the updated Tokyo Guidelines (TG13) with minor changes. TG13 presents new standards for the diagnosis, severity grading and management of acute cholecystitis. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

OBJECTIVE: To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA). METHODS: MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1). RESULTS: An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P=0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P=0.049) and between group 3 (40.5%; P=0.038) but not group 4 (36.5%; P=0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively. CONCLUSION: Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns.

BACKGROUND: Probiotics are microbial cell preparations or components of microbial cells that have a beneficial effect on the health and well being of the host. Probiotics may offer a safe intervention in acute infectious diarrhoea to reduce the duration and severity of the illness. OBJECTIVES: To assess the effects of probiotics in proven or presumed infectious diarrhoea. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group's trials register (December 2002), the Cochrane Controlled Trials Register (The Cochrane Library Issue 4, 2002), MEDLINE (1966 to 2002), EMBASE (1988 to 2002), and reference lists from studies and reviews. We also contacted organizations and individuals working in the field, and pharmaceutical companies manufacturing probiotic agents. SELECTION CRITERIA: Randomized controlled trials comparing a specified probiotic agent with placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial methodological quality and extracted data. MAIN RESULTS: Twenty-three studies met the inclusion criteria with a total of 1917 participants, mainly in countries with low overall mortality rates. Trials varied in relation to the probiotic(s) tested, dosage, methodological quality, and the diarrhoea definitions and outcomes. Probiotics reduced the risk of diarrhoea at 3 days (relative risk 0.66, 95% confidence interval 0.55 to 0.77, random effects model; 15 studies) and the mean duration of diarrhoea by 30.48 hours (95% confidence interval 18.51 to 42.46 hours, random effects model, 12 studies). Subgroup analysis by probiotic(s) tested, rotavirus diarrhoea, national mortality rates, and age of participants did not fully account for the heterogeneity. REVIEWERS' CONCLUSIONS: Probiotics appear to be a useful adjunct to rehydration therapy in treating acute, infectious diarrhoea in adults and children. More research is needed to inform the use of particular probiotic regimens in specific patient groups.

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.

BackgroundThe triglyceride glucose (TyG) index is an easily accessible surrogate marker of insulin resistance, an important pathway in the development of type 2 diabetes and cardiovascular diseases. However, the association of the TyG index with cardiovascular diseases and mortality has mainly been investigated in Asia, with few data available from other regions of the world. We assessed the association of insulin resistance (as determined by the TyG index) with mortality and cardiovascular diseases in individuals from five continents at different levels of economic development, living in urban or rural areas. We also examined whether the associations differed according to the country's economical development.MethodsWe used the TyG index as a surrogate measure for insulin resistance. Fasting triglycerides and fasting plasma glucose were measured at the baseline visit in 141 243 individuals aged 35–70 years from 22 countries in the Prospective Urban Rural Epidemiology (PURE) study. The TyG index was calculated as Ln (fasting triglycerides [mg/dL] x fasting plasma glucose [mg/dL]/2). We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random effects to test the associations between the TyG index and risk of cardiovascular diseases and mortality. The primary outcome of this analysis was the composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, and non-fatal myocardial infarction, or stroke). Secondary outcomes were non-cardiovascular mortality, cardiovascular mortality, all myocardial infarctions, stroke, and incident diabetes. We also did subgroup analyses to examine the magnitude of associations between insulin resistance (ie, the TyG index) and outcome events according to the income level of the countries.FindingsDuring a median follow-up of 13·2 years (IQR 11·9–14·6), we recorded 6345 composite cardiovascular diseases events, 2030 cardiovascular deaths, 3038 cases of myocardial infarction, 3291 cases of stroke, and 5191 incident cases of type 2 diabetes. After adjusting for all other variables, the risk of developing cardiovascular diseases increased across tertiles of the baseline TyG index. Compared with the lowest tertile of the TyG index, the highest tertile (tertile 3) was associated with a greater incidence of the composite outcome (HR 1·21; 95% CI 1·13–1·30), myocardial infarction (1·24; 1·12–1·38), stroke (1·16; 1·05–1·28), and incident type 2 diabetes (1·99; 1·82–2·16). No significant association of the TyG index was seen with non-cardiovascular mortality. In low-income countries (LICs) and middle-income countries (MICs), the highest tertile of the TyG index was associated with increased hazards for the composite outcome (LICs: HR 1·31; 95% CI 1·12–1·54; MICs: 1·20; 1·11–1·31; pinteraction=0·01), cardiovascular mortality (LICs: 1·44; 1·15–1·80; pinteraction=0·01), myocardial infarction (LICs: 1·29; 1·06–1·56; MICs: 1·26; 1·10–1·45; pinteraction=0·08), stroke (LICs: 1·35; 1·02–1·78; MICs: 1·17; 1·05–1·30; pinteraction=0·19), and incident diabetes (LICs: 1·64; 1·38–1·94; MICs: 2·68; 2·40–2·99; pinteraction <0·0001). In contrast, in high-income countries, higher TyG index tertiles were only associated with an increased hazard of incident diabetes (2·95; 2·25–3·87; pinteraction <0·0001), but not of cardiovascular diseases or mortality.InterpretationThe TyG index is significantly associated with future cardiovascular mortality, myocardial infarction, stroke, and type 2 diabetes, suggesting that insulin resistance plays a promoting role in the pathogenesis of cardiovascular and metabolic diseases. Potentially, the association between the TyG index and the higher risk of cardiovascular diseases and type 2 diabetes in LICs and MICs might be explained by an increased vulnerability of these populations to the presence of insulin resistance.FundingFull funding sources are listed at the end of the paper (see Acknowledgments).

BACKGROUND: Death from severe sepsis and septic shock is common, and researchers have explored whether antibodies to the endotoxins in some bacteria reduces mortality. OBJECTIVES: To estimate the effects of intravenous immunoglobulin (IVIG) in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group specialized register up to November 2001; the Cochrane Controlled Trials Register, The Cochrane Library issue 4, 2001; MEDLINE 1966 to November 2001; and EMBASE 1988 to September 2001. We contacted investigators active in the field for unpublished data. SELECTION CRITERIA: Randomised trials comparing intravenous immunoglobulin (monoclonal or polyclonal) with placebo or no intervention, in patients with bacterial sepsis or septic shock. DATA COLLECTION AND ANALYSIS: Inclusion criteria, trial quality assessment, and data abstraction were done in duplicate. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation. MAIN RESULTS: Twenty-seven out of 55 studies met our inclusion criteria. Pooled analysis of all types of IVIG preparations revealed a significant trend toward reduction of mortality (n= 8,856; RR=0.91; 95%CI 0.86-0.96). Overall mortality was reduced in patients who received polyclonal IVIG (n=492; RR=0.64; 95% CI 0.51 to 0.80). For the two high-quality trials on polyclonal IVIG, the RR for overall mortality was 0.30, but the confidence interval was wide (95% CI 0.09 to 0.99, n=91). Mortality was not reduced among patients who received monoclonal antibodies such as anti-endotoxins (n=2,826 in 5 good-quality studies; RR=0.97; 95% CI 0.88 to 1.07) or anti-cytokines (n=4,318; RR=0.93; 95% CI 0.86 to 1.01). A few studies measured secondary outcomes (deaths from sepsis or length of hospitalisation) but no differences in the intervention and control groups were identified except among those who received polyclonal IVIG, where sepsis-related mortality was significantly reduced (n=161; RR=0.35; 95% CI 0.18 to 0.69). REVIEWER'S CONCLUSIONS: Polyclonal IVIG significantly reduced mortality and and is a promising adjuvant in the treatment of sepsis and septic shock. However, all the trials were small and the totality of the evidence is insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.

Introduction: Systemic inflammation is associated with prognosis in solid tumors. The neutrophil-to-lymphocyte ratio (NLR) is a marker for the general immune response to various stress stimuli. Studies have shown correlation of NLR to outcomes in immune checkpoint blockade, peripheral neutrophil count to intratumor neutrophil population, and NLR to intratumoral levels of myeloid-derived suppressor cells. Studies have shown elevated peripheral blood regulator T cells accompanied by elevated NLR are associated with poor outcomes further highlighting the importance of inflammation in the prognosis of cancer patients. Methods: We performed a meta-analysis of published articles on the utility of baseline NLR in predicting outcomes in patients treated with immune checkpoint inhibitors (ICIs) using Review Manager, version 5.3. Seven studies on the prognostic utility of NLR in ICI treatment were included in this analysis. For outcomes of interest, the hazard ratios (HRs) were computed. Subgroup analyses were planned based on type of malignancy and type of immune checkpoint inhibitor. Results/discussion: A high NLR resulted in worse overall survival (OS) (HR, 1.92; 95% CI, 1.29–2.87; p =0.001) and progression-free survival (PFS; HR, 1.66; 95% CI, 1.38–2.01; p <0.00001) across types of malignancies studied (melanoma, non-small-cell lung cancer, and genitourinary cancer). Subgroup analysis across different types of malignancies treated with ICI showed similar results for OS and PFS. The single study on genitourinary cancers also showed worse OS and PFS (OS: HR, 1.82; 95% CI, 1.29–2.87; p =0.001 and PFS: HR, 1.83; 95% CI, 0.97–3.44; p =0.06). A high NLR also showed worse OS and PFS across all ICIs (ipilimumab, nivolumab, and unspecified or pooled pembrolizumab and nivolumab; OS: HR, 1.92; 95% CI, 1.29–2.87; p =0.001 and PFS: HR, 1.66; 95% CI, 1.38–2.01; p <0.00001). Subgroup analysis by type of ICI showed similar results. Conclusion: A high NLR is associated with poorer outcomes across studies. This shows that NLR has the potential as a readily available prognostic indicator for patients receiving ICI based on available studies. Studies utilizing more stringent design may serve to better determine the utility of this tool. Keywords: neutrophil-to-lymphocyte ratio, immunotherapy, biomarkers, inflammation

BACKGROUND: Mortality from sepsis and septic shock remains high. Results of trials on intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have been conflicting. This is an update of a Cochrane review that was originally published in 1999 and updated in 2002 and 2010. OBJECTIVES: To estimate the effects of IVIG as adjunctive therapy in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1966 to December 2012), and EMBASE (1988 to December 2012). We contacted investigators in the field for unpublished data. The original search was performed in 1999 and updated in 2002 and 2008. SELECTION CRITERIA: We included randomized controlled trials comparing IVIG (monoclonal or polyclonal) with placebo or no intervention in patients of any age with bacterial sepsis or septic shock. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the studies for inclusion and undertook methodologic quality assessment and data abstraction. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation. MAIN RESULTS: We included 43 studies that met our inclusion criteria in this updated review out of 88 potentially eligible studies. The studies included a large polyclonal IVIG trial in neonates that was concluded in 2011 and classified as ongoing in the 2010 version of this review. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality in adults with sepsis compared to placebo or no intervention (relative risk (RR) 0.81; 95% confidence interval (CI) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates, which now includes the recently concluded large polyclonal IVIG trial, showed no significant reduction in mortality for standard IVIG (RR 1.00; 95% CI 0.92 to 1.08; five trials, n = 3667) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; three trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; five trials, n = 945) and neonates (RR 1.01; 95% CI 0.93 to 1.09; three trials, n = 3561). Mortality was not reduced among patients (eight trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (nine trials, n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97). AUTHORS' CONCLUSIONS: Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.

AIMS: Summating risk factor burden is a useful approach in the assessment of cardiovascular risk among apparently healthy individuals. We aimed to derive and validate a new score for myocardial infarction (MI) risk using modifiable risk factors, derived from the INTERHEART case-control study (n = 19 470). METHODS AND RESULTS: Multiple logistic regression was used to create the INTERHEART Modifiable Risk Score (IHMRS). Internal validation was performed using split-sample methods. External validation was performed in an international prospective cohort study. A risk model including apolipoproteins, smoking, second-hand smoke exposure, hypertension, and diabetes was developed. Addition of further modifiable risk factors did not improve score discrimination in an external cohort. Split-sample validation studies showed an area under the receiver-operating characteristic (ROC) curve c-statistic of 0.71 [95% confidence interval (CI): 0.70, 0.72]. The IHMRS was positively associated with incident MI in a large cohort of people at low risk for cardiovascular disease [12% increase in MI risk (95% CI: 8, 16%) with a 1-point increase in score] and showed appropriate discrimination in this cohort (ROC c-statistic 0.69, 95% CI: 0.64, 0.74). Results were consistent across ethnic groups and geographic regions. A non-laboratory-based score is also supplied. CONCLUSIONS: Using multiple modifiable risk factors from the INTERHEART case-control study, we have developed and validated a simple score for MI risk which is applicable to an international population.

The International League Against Epilepsy (ILAE) has updated the operational classification of epileptic seizures, building upon the framework established in 2017. This revision, informed by the implementation experience, involved a working group appointed by the ILAE Executive Committee. Comprising 37 members from all ILAE regions, the group utilized a modified Delphi process, requiring a consensus threshold of more than two thirds for any proposal. Following public comments, the Executive Committee appointed seven additional experts to the revision task force to address and incorporate the issues raised, as appropriate. The updated classification maintains four main seizure classes: Focal, Generalized, Unknown (whether focal or generalized), and Unclassified. Taxonomic rules distinguish classifiers, which are considered to reflect biological classes and directly impact clinical management, from descriptors, which indicate other important seizure characteristics. Focal seizures and those of unknown origin are further classified by the patient's state of consciousness (impaired or preserved) during the seizure, defined operationally through clinical assessment of awareness and responsiveness. If the state of consciousness is undetermined, the seizure is classified under the parent term, that is, the main seizure class (focal seizure or seizure of unknown origin). Generalized seizures are grouped into absence seizures, generalized tonic-clonic seizures, and other generalized seizures, now including recognition of negative myoclonus as a seizure type. Seizures are described in the basic version as with or without observable manifestations, whereas an expanded version utilizes the chronological sequence of seizure semiology. This updated classification comprises four main classes and 21 seizure types. Special emphasis was placed on ensuring translatability into languages beyond English. Its aim is to establish a common language for all health care professionals involved in epilepsy care, from resource-limited areas to highly specialized centers, and to provide accessible terms for patients and caregivers.

Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue. This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3I highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.

OBJECTIVE: To describe intracochlear insertion trauma caused by three perimodiolar cochlear implant electrodes. STUDY DESIGN: Descriptive histological study of 15 human cadaver temporal bones. METHODS: Fifteen cadaver temporal bones underwent surface preparation and were implanted with one of the following perimodiolar electrode arrays: Combi 40+PM (MedEl Corporation), HiFocus II (Advanced Bionics Corporation), or Contour (Cochlear Corporation). A cryosectioning technique was used to study horizontal sections at 200 microm intervals with the electrode in place. Image-enhanced videofluoroscopy and computer-assisted morphometrics were used to assess the mechanism of insertion trauma and to determine electrode position within the modiolus. RESULTS: Histological examination revealed varying degrees of damage to the spiral ligament, basilar membrane, and osseous spiral lamina. Using a novel grading system for electrode trauma, there was no statistically significant difference among the three electrodes. A literature search of histological studies of a commonly used "standard" electrode showed damage equal to or greater than that seen in the current study. CONCLUSIONS: Insertion trauma caused by periomodiolar electrodes occurs to an acceptable degree. Refinement of electrodes based on mechanisms of trauma may be able to further reduce damage.

Importance: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. Observations: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. Conclusions and Relevance: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients.