Pendyal A, Ross JS.

This Arts and Medicine essay reviews The Bleeding Edge, a Netflix documentary about the medical device industry and the harms that can come to patients when innovation, regulatory approval, and adoption of devices in practice outpace evidence of their safety and benefit.

“How beautiful are thy feet, with shoes, O! Prince’s daughter,” says the Song of Solomon, and it must be confessed as a fact true of our time that modern feet must be hidden by shoes to give an approach in appearance to a perfect classic standard. Toes twisted out of shape, thick projections at points of contact, clubbed nails, corns in various uncanny situations, and bunions on the joints, make the actual foot so far from being a thing of beauty that it is only to be viewed in private and then by the chiropodist.

Johnston S.

This Viewpoint discusses the conflict between the role of academic medical centers as providers of complex uncompensated care, and the large profit margins they realize from expensive fee-for-service clinical activity that puts them at odds with attempts to reorganize medicine to provide value-based care.

In the Viewpoint entitled “The True Cost of Measles Outbreaks During the Postelimination Era,” published in the March 26, 2019, issue of JAMA, an additional funding source is being added. In the Funding/Support section, at the end of the section, the following should appear “; and by grant R01AI125405 from the National Institutes of Health.” In the Role of the Funder/Sponsor section, the section heading should be plural so “Role of the Funders/Sponsors” and the word “sponsor” should be “sponsors.” This article was corrected online.

Castillo-Mancilla J.

Pokharel S, White L, Aguas R, et al.

AbstractBackgroundIn the absence of proper guidelines and algorithms, available rapid diagnostic tests (RDTs) for common acute undifferentiated febrile illnesses (AUFI) are often used inappropriately.MethodsUsing prevalence data of five common febrile illnesses from India and Cambodia, and performance characteristics (sensitivity and specificity) of relevant pathogen-specific RDTs, we used a mathematical model to predict the probability of correct identification of each disease when diagnostic testing occurs either simultaneously or sequentially in various algorithms. We developed a web-based application of the model so as to visualise and compare output diagnostic algorithms when different disease prevalence and test performance characteristics are introduced.ResultsDiagnostic algorithms with appropriate sequential testing predicted correct identification of aetiology in 74% and 89% of patients in India and Cambodia respectively compared to 46% and 49% with simultaneous testing. The optimally performing sequential diagnostic algorithms differed in India and Cambodia due to varying disease prevalence.ConclusionSimultaneous testing is not appropriate for the diagnosis of AUFIs with presently available tests, which should deter the unsupervised use of multiplex diagnostic tests. The implementation of adaptive algorithms can predict better diagnosis and add value to the available RDTs. The web application of the model can serve as a tool to identify the optimal diagnostic algorithm in different epidemiological settings, whilst taking into account the local epidemiological variables and accuracy of available tests.

Purohit, Prashant J.; Elkomy, Mohammed H.; Frymoyer, Adam; Sutherland, Scott M.; Drover, David R.; Hammer, Gregory B.; Su, Felice

Objectives: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model. Design: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole). Setting: University research laboratory. Patients: None. Interventions: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug. Measurements and Main Results: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates. Conclusions: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy. Drs. Purohit and Elkomy shared equally in the first authorship. Drs. Purohit and Elkomy contributed equally to be the first author on this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grant from the Child Health Research Institute, Lucile Packard Foundation for Children’s Health and the Stanford Clinical and Translational Science Award UL1 TR001085. Dr. Purohit disclosed that this work was supported by the National Institutes of Health and the Child Health Research Institute, Lucile Packard Foundation for Children’s Health and the Stanford Clinical and Translational Science Award UL1 TR001085. Dr. Drover received funding from Masimo. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Stanford University School of Medicine. For information regarding this article, E-mail: drpurohit22@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Cortés, Jorge A.; Roncancio, Álvaro; Uribe, Luis Guillermo; Cortés-Luna, Carlos Fernando; Montoya, José G.

Purpose of review To discuss available information on the effectiveness of anti-toxoplasma therapy for ocular toxoplasmosis and to provide clinicians with a practical approach to the disease. Recent findings Only eleven randomized studies were identified. In the three studies for acute retinitis, there was a clear trend in favor of treatment. In the two studies for the prevention of recurrences, trimethoprim–sulfamethoxazole prophylaxis was superior to placebo. In the six studies comparing different regimens, there was no statistically significant difference between the regimens. In the setting of acute posterior uveitis suspected to be caused by toxoplasma, serological testing should always be obtained, and anti-toxoplasma drug treatment, and corticosteroids should be instituted for at least 6 weeks. Toxoplasmic chorioretinitis during pregnancy represents a particular challenge. Summary Treatment with at least two drugs and corticosteroids should be offered to patients with active toxoplasmic chorioretinitis. Pregnant women with confirmed acute infection and concomitant acute retinitis should be treated for the ocular lesion(s) and to prevent vertical transmission. Pregnant women with chronic Toxoplasma infection acquired prior to gestation and concomitant retinitis by reactivation should be treated for the retinitis and monitored for vertical transmission. Correspondence to Jorge A. Cortés, MD, Street address: Oficina 510, Edificio Facultad de Medicina, Ciudad Universitaria, Cra 30 no 45 03, Bogotá, Colombia. Tel.: +57 1 3165000x15011;. e-mail: jacortesl@unal.edu.co Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Nogueira LM, Sahar L, Efstathiou JA, et al.

This study uses National Cancer Database data to estimate associations between hurricane disaster declarations, which could disrupt electrical power, and survival of patients undergoing radiotherapy for nonoperative locally advanced non–small cell lung cancer between 2004 and 2014.

Kahn JM, Davis BS, Yabes JG, et al.

This cohort study uses hospital discharge data to compare 30-day in-hospital mortality of patients with sepsis in New York State before vs after implementation of regulations mandating rapid administration of antibiotics and fluid resuscitation and compares those data with mortality in 4 comparison states (Florida, Maryland, Massachusetts, and New Jersey) without such a mandate.

Gubareva L, Fry A.

Drug resistance is a topic of significant concern in the treatment of infectious diseases caused by rapidly evolving RNA viruses that can persist (eg, human immunodeficiency virus and hepatitis C virus) or reinfect (eg, influenza virus). Combination drug therapy is standard of care for the treatment of infections by rapidly mutating RNA viruses [1, 2]. However, it is not a common approach for treating influenza virus infections, partly because of the limited number of anti-influenza drugs and drug targets. We now know that all of the classes of anti-influenza drugs—M2 blockers, neuraminidase inhibitors (NAIs), and the newly licensed cap-dependent endonuclease inhibitor (baloxavir marboxil)—have low genetic barriers to resistance: 1 or 2 amino acid substitutions are sufficient to gain resistance [3, 4].

L. S. Karan et al.

Voelker R.

In this Medical News article, experts discuss how—or whether—the United States should have a national conversation about death and dying.

Gonzalez C, Quackenbush N, Stancliff S.

To the Editor In their critique of the availability of medical marijuana for patients suffering from chronic pain or struggling with opioid use disorder, Drs Humphreys and Saitz omitted important facts about the New York State Medical Marijuana Program, the limited availability of medication for addiction treatment (also known as medication-assisted treatment), and why clinical research on marijuana is so sparse.

Humphreys K, Saitz R.

In Reply Dr Gonzalez and colleagues provide detail regarding the New York State Medical Marijuana Program, noting that dispensaries overseen by pharmacists sell regulated products and that certifying practitioners must consult a prescription monitoring program. Some regulation of putatively medical cannabis is clearly better than none, but the New York standards are well below those set for the practice of medicine generally, in which preferred prescribed medications have clinical trial–derived evidence of efficacy and safety in specific doses for specific conditions.

Babich T, Naucler P, Valik J, et al.

AbstractBackgroundThe optimal antibiotic regimen for Pseudomonas aeruginosa bacteremia is controversial. Though beta-lactam monotherapy is common, data to guide the choice between antibiotics are scarce. We aimed to compare ceftazidime, carbapenems, and piperacillin-tazobactam as definitive monotherapy.MethodsA multinational retrospective study (9 countries, 25 centers), including hospitalized patients with P . aeruginosa bacteremia treated with beta-lactam monotherapy during 2009-2015. The primary outcome was 30-day all-cause mortality. Univariate and multivariate analyses, including propensity adjusted analysis, were conducted introducing monotherapy type as an independent variable.ResultsWe included 767 patients. Thirty-day mortality was 37/213 (17.4%) in the ceftazidime group; 42/210 (20%) in the carbapenem group, and 55/344 (16%) in the piperacillin-tazobactam group. Type of monotherapy was not significantly associated with mortality in either univariate, multivariate or propensity adjusted analyses (odds ratio [OR] 1.14, 95% confidence interval [CI] 0.52-2.46 for ceftazidime, OR 1.3, 95% CI 0.67-2.51 for piperacillin-tazobactam with carbapenems as reference in propensity adjusted multivariate analysis, 542 patients). No significant difference between antibiotics was demonstrated for clinical failure, microbiological failure, or adverse events. Isolation of P. aeruginosa with new resistance to antipseudomonal drugs was significantly more frequently with carbapenems (36/206, 17.5% versus ceftazidime 25/201, 12.4% and piperacillin-tazobactam 28/332, 8.4%, p=0.007).ConclusionsNo significant difference in mortality, clinical, and microbiological outcomes or adverse events was demonstrated between ceftazidime, carbapenems and piperacillin-tazobactam as definitive treatment of P. aeruginosa bacteremia. Higher rates of resistant P. aeruginosa after patients were treated with carbapenems, along with the general preference for carbapenem-sparing regimens, suggests using ceftazidime or piperacillin-tazobactam for treating susceptible infection.

Abstract Background Cervicofacial necrotizing fasciitis (NF) is a rare life-threatening infection in the head and neck region that characteristically spreads along the fascial planes to involve subcutaneous tissues, fascia and fat, however, in late stages it can involve muscles and skin. The aim of this study was to determine the occurrence of cervicofacial NF among patients attending treatment at the Muhimbili National Hospital (MNH). Methods This was a prospective descriptive cross-sectional hospital-based study which was carried at Muhimbili National Hospital (MNH) from May 2013 to April 2014. It included 42 patients with cervicofacial NF. They were interviewed for demographic information, chief complaints, symptoms, duration and treatment received before reporting at MNH. A thorough assessment of general health condition of the patients and laboratory investigations were followed by management according to MNH protocol. Data obtained from these patients were analyzed using Statistical Package for Social Sciences SPSS 20. Results During the study period, 151 patients reported at MNH with odontogenic infections. A total of 42 (27.8%) patients satisfied our diagnostic criteria for cervicofacial NF. The age range was 15 years to 83 years (mean 43.95, SD +/− 16.16). Greater (35.7%) proportion was in the age group of 30–39 years with 31 (73.8%) males and 11 (27.2%) females making a male to female ratio of 2.8:1. Fifteen (35.7%) patients had at least one co-existing systemic condition, which included anaemia in 5 (11.9%) patients, followed by diabetes mellitus (DM) and malnutrition 4 (9.5%) patients each and HIV infection 2 (4.8%) patients. Others were combination of; HIV infection and malnutrition, HIV infection and anaemia and diabetes mellitus and anaemia each in one (2.4%) patient. There was a mortality of 42.9% comprising of 14 (33.3%) males and 4 (9.6%) females. Conclusions Cervicofacial NF is a polymicrobial infection, requiring surgery, antibiotics and management of co-existing systemic conditions. Anaemia, diabetes mellitus and malnutrition were the main co-existing systemic conditions. The rather high mortality was mainly attributable to late reporting.…

Abstract Background Plasmodium falciparum merozoite surface protein-1 (PfMSP-1) and -2 (PfMSP-2) are major blood-stage vaccine candidate antigens. Understanding the genetic diversity of the genes, pfmsp-1 and pfmsp-2, is important for recognizing the genetic structure of P. falciparum, and the development of an effective vaccine based on the antigens. In this study, the genetic diversities of pfmsp-1 and pfmsp-2 in the Myanmar P. falciparum were analysed. Methods The pfmsp-1 block 2 and pfmsp-2 block 3 regions were amplified by polymerase chain reaction from blood samples collected from Myanmar patients who were infected with P. falciparum in 2013–2015. The amplified gene fragments were cloned into a T&A vector, and sequenced. Sequence analysis of Myanmar pfmsp-1 block 2 and pfmsp-2 block 3 was performed to identify the genetic diversity of the regions. The temporal genetic changes of both pfmsp-1 and pfmsp-2 in the Myanmar P. falciparum population, as well as the polymorphic diversity in the publicly available global pfmsp-1 and pfmsp-2, were also comparatively analysed. Results High levels of genetic diversity of pfmsp-1 and pfmsp-2 were observed in the Myanmar P. falciparum isolates. Twenty-eight different alleles of pfmsp-1 (8 for K1 type, 14 for MAD20 type, and 6 for RO33 type) and 59 distinct alleles of pfmsp-2 (18 for FC27, and 41 for 3D7 type) were identified in the Myanmar P. falciparum population in amino acid level. Comparative analyses of the genetic diversity of the Myanmar pfmsp-1 and pfmsp-2 alleles in the recent (2013–2015) and past (2004–2006) Myanmar P. falciparum populations indicated the dynamic genetic expansion of the pfmsp-1 and pfmsp-2 in recent years, suggesting that a high level of genetic differentiation and recombination of the two genes may be maintained. Population genetic structure analysis of the global pfmsp-1 and pfmsp-2 also suggested that a high level of genetic diversity of the two genes was found in the global P. falciparum population. Conclusion Despite the recent remarkable decline of malaria cases, the Myanmar P. falciparum population still remains of sufficient size to allow the generation and maintenance of genetic diversity. The high level of genetic diversity of pfmsp-1 and pfmsp-2 in the global P. falciparum population emphasizes the necessity for continuous monitoring of the genetic diversity of the genes for better understanding of the genetic make-up and evolutionary aspect of the genes in the global P. falciparum population.…

Abstract Background In recent years, the scale-up of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) has greatly reduced malaria transmission. However, malaria remains a global public health concern with the majority of the disease burden in sub-Saharan Africa. Insecticide resistance is a growing problem among Anopheles vector populations, with potential implications for the continued effectiveness of available control interventions. Improved understanding of current resistance levels and underlying mechanisms is essential to design appropriate management strategies and to mitigate future selection for resistance. Methods Anopheles gambiae sensu lato mosquitoes were collected from three villages in Faranah Prefecture, Guinea and their levels of susceptibility to seven insecticides were measured using CDC resistance intensity bioassays. Synergist assays with piperonyl butoxide (PBO) were also undertaken to assess the role of elevated mixed-function oxidases in resistance. Five hundred and sixty-three mosquitoes underwent molecular characterization of vector species, presence of target site mutations (L1014F kdr, N1575Y and G119S Ace-1), Plasmodium falciparum infection, and relative expression of three metabolic genes (CYP6M2, CYP6P3 and GSTD3). Results In Faranah, resistance to permethrin and deltamethrin was observed, as well as possible resistance to bendiocarb. All assayed vector populations were fully susceptible to alpha-cypermethrin, pirimiphos-methyl, clothianidin and chlorfenapyr. Plasmodium falciparum infection was detected in 7.3% (37/508) of mosquitoes tested. The L1014F kdr mutation was found in 100% of a sub-sample of 60 mosquitoes, supporting its fixation in the region. The N1575Y mutation was identified in 20% (113/561) of individuals, with ongoing selection evidenced by significant deviations from Hardy–Weinberg equilibrium. The G119S Ace-1 mutation was detected in 62.1% (18/29) of mosquitoes tested and was highly predictive of bendiocarb bioassay survival. The metabolic resistance genes, CYP6M2, CYP6P3 and GSTD3, were found to be overexpressed in wild resistant and susceptible An. gambiae sensu stricto populations, compared to a susceptible G3 colony. Furthermore, CYP6P3 was significantly overexpressed in bendiocarb survivors, implicating its potential role in carbamate resistance in Faranah. Conclusions Identification of intense resistance to permethrin and deltamethrin in Faranah, is of concern, as the Guinea National Malaria Control Programme (NMCP) relies exclusively on the distribution of pyrethroid-treated LLINs for vector control. Study findings will be used to guide current and future control strategies in the region.…

Sancar F.

A novel antibody-drug conjugate (ADC) for adults with refractory or relapsing diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, has received accelerated FDA approval. Up to 40% of patients with DLBCL will relapse.

Abstract Background The outcomes of deep-seated abscesses attributed to chronic disseminated candidiasis (CDC) in patients with hematological malignancies have rarely been reported in recent years. Methods We retrospectively reviewed and analyzed the data of patients with hematological malignancies who received a diagnosis of CDC at a medical center in Taiwan between 2008 and 2013. Results Sixty-one patients (32 men and 29 women) were diagnosed with CDC. The median age was 51 years (range: 18–83). The overall incidence of CDC was 1.53 per 100 patient-years in patients with hematological malignancies between 2008 and 2013. The highest incidence of CDC was 4.3 per 100 patient-years for acute lymphoblastic leukemia, followed by 3.6 for acute myeloid leukemia. We detected 3 (4.9%) proven, 13 (21.3%) probable, and 45 (73.8%) possible cases of CDC. A total of 13 patients had positive blood cultures for Candida species: C. tropicalis (8), C. albicans (2), C. glabrata (2), and C. famata (1). The median duration of antifungal treatment was 96 days (range: 7–796 days). Serial imaging studies revealed that the resolution rate of CDC was 30.0% at 3 months and 54.3% at 6 months. Five patients (8.2%) had residual lesions that persisted beyond one year. A multivariate analysis of the 90-day outcome revealed that shock was the only independent prognostic factor of 90-day survival in patients with CDC. Conclusion The incidence of CDC did not decrease between 2008 and 2013. Patients with acute leukemia had a higher risk of CDC than those with other hematological malignancies. Imaging studies conducted at 6 months after diagnosis revealed that only half of the patients showed complete resolution. CDC requires prolonged treatment, and serial imaging at 6 months interval is suggested. Shock is the only independent prognostic factor of 90-day survival in patients with CDC.…

Drain P, Kubiak R, Siriprakaisil O, et al.

AbstractBackgroundDirect measurement of tenofovir (TFV) in urine could be an objective measure to monitor adherence to pre-exposure prophylaxis (PrEP) or TFV-based antiretroviral therapy (ART). We describe urine TFV concentrations in adults with controlled levels of adherence to advance development and enable interpretation of point-of-care urine assays.MethodsWe conducted a three-arm randomized, open-label, pharmacokinetic study of tenofovir disoproxil fumarate (TDF) 300mg/emtricitabine (FTC) 200mg among HIV-uninfected adults. Participants were randomized to receive controlled TDF/FTC dosing as: (1) ‘perfect’ adherence (daily), (2) ‘moderate’ adherence (four doses/week), or (3) ‘low’ adherence (two doses/week). We obtained trough spot urine and plasma samples during a six-week directly-observed therapy period and a four-week washout period. TFV concentrations were compared between adherence arms using one-way analysis of variance.ResultsAmong 28 participants, mean age was 33 years and 16 (57%) were male. Correlation between TFV plasma and urine concentrations was strong (rho=0.78; p

Kuehn B.

Isolating adults with respiratory symptoms resulting from Nipah virus infection may help stem the spread of the virus, a New England Journal of Medicinestudy suggests.

Sancar F.

The FDA has authorized marketing of the first medical device for adolescents with abdominal pain associated with irritable bowel syndrome (IBS). The device, which is available by prescription only, is indicated for patients aged 11 through 18 years.

Majeed, Ammar; Majumdar, Avik; Bailey, Michael; Kemp, William; Bellomo, Rinaldo; Pilcher, David; Roberts, Stuart K.

Objectives: We aimed to describe changes over time in admissions and outcomes, including length of stay, discharge destinations, and mortality of cirrhotic patients admitted to the ICU for variceal bleeding, and to compare it to the outcomes of those with other causes of ICU admissions. Design: Retrospective analysis of data captured prospectively in the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database. Settings: One hundred eighty-three ICUs in Australia and New Zealand. Patients: Consecutive admissions to these ICUs for upper gastrointestinal bleeding related to varices in patients with cirrhosis between January 1, 2005, and December 31, 2016. Interventions: None. Measurements and Main Results: ICU admissions for variceal bleeding in cirrhotic patients accounted for 4,003 (0.6%) of all 720,425 nonelective ICU admissions. The proportion of ICU admissions for variceal bleeding fell significantly from 0.8% (83/42,567) in 2005 to 0.4% (53/80,388) in 2016 (p < 0.001). Hospital mortality rate was significantly higher within admissions for variceal bleeding compared with nonelective ICU admissions (20.0% vs 15.7%; p < 0.0001), but decreased significantly over time, from 24.6% in 2005 to 15.8% in 2016 (annual decline odds ratio, 0.93; 95% CI, 0.90–0.96). There was no difference in the reduction in mortality from variceal bleeding over time between liver transplant and nontransplant centers (p = 0.26). Conclusions: Admission rate to ICU and mortality of cirrhotic patients with variceal bleeding has declined significantly over time compared with other causes of ICU admissions with the outcomes comparable between liver transplant and nontransplant centers. Dr. Majeed helped with drafting of the article, interpretation of the data, and study concept. Dr. Majumdar helped with preparation and critical review of the article. Dr. Bailey helped with data acquisition, statistical analysis, and critical review of the article. Drs. Kemp and Bellomo helped with preparation and critical review of the article. Mr. Pilcher helped with data acquisition, review of the article, interpretation of the data, and study concept. Dr. Roberts helped with preparation and critical review of the article, and study concept. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grants from the Alfred Hospital Department of Gastroenterology and the Australian and New Zealand Intensive Care Research Centre. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: a.majeed@alfred.org.au Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Hayden M.

whole genome sequencingsurveillanceoutbreak detectionnosocomialinfection prevention…

Abstract Background Tuberculosis (TB) is the infectious disease that kills the most people worldwide. The use of geoepidemiological techniques to demonstrate the dynamics of the disease in vulnerable communities is essential for its control. Thus, this study aimed to identify risk clusters for TB deaths and their variation over time. Methods This ecological study considered cases of TB deaths in residents of Londrina, Brazil between 2008 and 2015. We used standard, isotonic scan statistics for the detection of spatial risk clusters. The Poisson discrete model was adopted with the high and low rates option used for 10, 30 and 50% of the population at risk, with circular format windows and 999 replications considered the maximum cluster size. Getis-Ord Gi* (Gi*) statistics were used to diagnose hotspot areas for TB mortality. Kernel density was used to identify whether the clusters changed over time. Results For the standard version, spatial risk clusters for 10, 30 and 50% of the exposed population were 4.9 (95% CI 2.6–9.4), 3.2 (95% CI: 2.1–5.7) and 3.2 (95% CI: 2.1–5.7), respectively. For the isotonic spatial statistics, the risk clusters for 10, 30 and 50% of the exposed population were 2.8 (95% CI: 1.5–5.1), 2.7 (95% CI: 1.6–4.4), 2.2 (95% CI: 1.4–3.9), respectively. All risk clusters were located in the eastern and northern regions of the municipality. Additionally, through Gi*, hotspot areas were identified in the eastern and western regions. Conclusions There were important risk areas for tuberculosis mortality in the eastern and northern regions of the municipality. Risk clusters for tuberculosis deaths were observed in areas where TB mortality was supposedly a non-problem. The isotonic and Gi* statistics were more sensitive for the detection of clusters in areas with a low number of cases; however, their applicability in public health is still restricted.…

Abstract Background Malaria vector control is dependent on chemical insecticides applied to walls by indoor residual spraying or on long-lasting insecticidal nets. The emergence and spread of insecticide resistance in major malaria vectors may compromise malaria control and elimination efforts. The aim of this study was to estimate a diagnostic dose for chlorfenapyr (class: pyrrole) and clothianidin (class: neonicotinoid) and assess the baseline susceptibility of three major Anopheles malaria vectors of western Kenya to these two insecticides. Methods The Centers for Disease Control and Prevention (CDC) bottle assay was used to determine the diagnostic doses of chlorfenapyr and clothianidin insecticides against the susceptible Kisumu strain of Anopheles gambiae. Probit analysis was used to determine the lethal doses at which 50% (LD50) and 99% (LD99) of the susceptible mosquitoes would be killed 24, 48 and 72 h following exposure for 1 h. Insecticidal efficacy of chlorfenapyr, clothianidin and the pyrethroid deltamethrin was then evaluated against field collected female Anopheles mosquitoes sampled from Nyando, Bumula and Ndhiwa sub-Counties in western Kenya. Members of Anopheles funestus and An. gambiae complexes were identified using polymerase chain reaction (PCR). Results The determined diagnostic doses of chlorfenapyr and clothianidin insecticides were 50 µg/bottle and 150 µg/bottle, respectively, for An. gambiae, Kisumu strain. When exposed to the diagnostic dose of each insecticide, Anopheles malaria vector populations in western Kenya were susceptible to both insecticides with 100% mortality observed after 72 h. Mortality of mosquitoes exposed to deltamethrin increased over time but did not reach 100%. Mortality of Anopheles arabiensis from Nyando exposed to deltamethrin was 83% at 24 h, 88% at 48 h and 94.5% at 72 h while An. funestus from Ndhiwa was 89% at 24 h, 91.5% at 48 h and 94.5% at 72 h. Conclusion Mosquitoes of western Kenya, despite being resistant to pyrethroids, are susceptible to chlorfenapyr and clothianidin. Field evaluations of the formulated product are needed.…

Micieli R, Micieli JA.

A 39-year-old woman with a history of palmar and axillary hyperhidrosis had anisocoria more pronounced in bright lighting conditions. She appeared well; denied double vision, ptosis, headache, or weakness; had normal visual acuity; and her neurologic examination was unremarkable. What is the diagnosis and what would you do next?…

Garrouste-Orgeas M, Flahault C, Vinatier I, et al.

This randomized clinical trial compared the effects of a diary filled out by clinicians and family members during an intensive care unit (ICU) stay to ground their memory of events after discharge vs usual care on symptoms of posttraumatic stress disorder, anxiety, and depression in patients and family members after discharge.

Rosa R, Falavigna M, da Silva D, et al.

This cluster-crossover randomized clinical trial compares the effects of a flexible visitation policy (up to 12 hours per day) vs a standard visitation policy (up to 4.5 hours per day) on delirium incidence among ICU patients.

Khagayi S, Omore R, Otieno G, et al.

AbstractBackgroundRotavirus remains a leading cause of diarrheal illness and death among children worldwide. Data on rotavirus vaccine effectiveness in sub-Saharan Africa are limited. Kenya introduced monovalent rotavirus vaccine (RV1) in July 2014. We assessed RV1 effectiveness against rotavirus-associated hospitalization in Kenyan children.MethodsBetween July-2014 and December-2017, we conducted surveillance for acute gastroenteritis (AGE) in three hospitals across Kenya. We analysed data from children age-eligible for ≥1 RV1 dose, with stool tested for rotavirus and confirmed vaccination history. We compared RV1 coverage among those who tested rotavirus-positive (cases) versus rotavirus-negative (controls) using multivariable logistic regression; effectiveness was 1-adjusted odds ratio for vaccination x100%.ResultsAmong 677 eligible children, 110 (16%) were rotavirus-positive. Vaccination data were available for 91 (83%) cases; 51 (56%) had received 2 RV1 doses and 33 (36%) 0 doses. Among 567 controls, 418 (74%) had vaccination data; 308 (74%) had 2 doses and 69 (16%) 0 doses. Overall 2-dose effectiveness was 64% (95% confidence interval [CI]: 35-80%); for children aged

Abstract Background The virological or clinical relapse is common in chronic hepatitis B (CHB) patients after stopping long-term nucleos(t)ide analogue (NA) therapy. Soluble growth stimulation expressed gene 2 (sST2), one of the Toll-like/interleukin-1 receptor members, is involved in a variety of inflammatory processes and immune responses. However, the expression and function of serum sST2 in CHB patients after stopping NA treatment remains unknown. Methods A total of 91 non-cirrhotic Asian patients with CHB who discontinued NA therapy according to international guidelines were prospectively followed up to 240 weeks. All patients were divided into clinical relapse group and non-clinical relapse (including sustained virological response and only virological relapse) group according HBV DNA and ALT levels. The serum levels of sST2 of all participants were determined by ELISA and compared between each two groups. Results Clinical relapse occurred in 26 patients and virological relapse occurred in 57 patients. We found that there was a positive correlation between sST2 expression and HBsAg, ALT, HBV DNA, and anti-HBc levels in CHB patients after discontinuation of NA treatment. Levels of serum sST2 in clinical relapse patients showed a rising trend and most patients showed peak sST2 levels at the point of clinical relapse. Moreover, the sST2 levels of clinical relapse group at week 12, week 24 and week 48 were relatively higher than non-clinical relapse group. However, the level of sST2 at the end of treatment was not an effective biological marker for the early prediction of clinical relapse after discontinuation of long-term NA therapy. Conclusions In conclusion, we found that an increase in sST2 in clinical relapse patients might be associated with an inflammation-related immune response after discontinuation of NA treatment. Trial registration The trial was retrospectively registered at Chinese Clinical Trial Registry: ChiCTR-OOC-17013970. Registration date: December 15, 2017.…

D. Vijaykrishna et al.

Perakslis E, Califf RM.

This Viewpoint discusses the rapidly growing threat to public health that the dissemination of medical misinformation enables and the active measures that must be taken to stop it.

Jahan R, Saver JL, Schwamm LH, et al.

This cohort study uses data from the Get With the Guidelines-Stroke registry to report associations between time to treatment and functional outcomes among patients in clinical practice with acute ischemic stroke treated with endovascular recanalization.

Muth CC.

Five randomized clinical trials, published in 2015, demonstrated the benefit of endovascular therapy in appropriately selected patients with acute ischemic stroke due to large vessel occlusion, and a subsequent individual patient data meta-analysis of these trials indicated that the benefit associated with endovascular therapy was greater the earlier that endovascular reperfusion was achieved. Since publication of these important trials, the use of endovascular therapy in the United States has significantly increased, and efforts are ongoing to maximize the potential benefits of endovascular therapy for the greatest number of eligible patients possible.

Sancar F.

A monoclonal antibody that the FDA approved last year to prevent chronic and episodic migraine has now received approval to treat episodic cluster headache in adults. The drug blocks calcitonin gene-related peptide ligand—a potent vasodilator that modulates nociceptive trigeminal neurons involved in the pathophysiology of cluster headaches. Patients can self-inject galcanezumab, marketed as Emgality.

Abstract Background The aim of this study was to establish a set of assessment methods suitable for evaluating the complex indoor environment of hospital wards and to ascertain the composition of bacteria and microbial ecology of hospital wards. Methods Colony-forming units (CFUs), PM2.5 detection, real-time PCR, and adenosine triphosphate (ATP) bioluminescence assay were employed to evaluate the complexity of indoor air in 18 wards of nine departments in a hospital and two student dormitories in a university. Subsequently, the microbial samples were quantified and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results Although the studied indices were relatively independent, the PM2.5 content was correlated with bacterial CFUs determined by passive sedimentation method, bacterial and fungal counts measured by real-time PCR, and ATP bioluminescence assay. The composition of microorganisms in the air of hospital wards differed from that in the air of student dormitories. The dominant genera in hospital wards were Staphylococcus (39.4%), Micrococcus (21.9%), Corynebacterium (11.7%), Kocuria (4.4%), Bacillus (2.9%), Streptococcus (1.6%), Moraxella (1.6%), and Enterococcus (1.3%), and the microbial ecology differed between Respiration Dept. III and other hospital departments. Additionally, 11.1 and 27.3% of bacteria in hospital wards and student dormitories were not identified, respectively. Conclusions Assessment of environmental quality of hospital wards should be based on comprehensive analysis with multiple indicators. There may be imbalances in the microbial diversity in the hospital wards, therefore, monitoring of the environmental quality of hospitals is important in the prevention of nosocomial infections.…

Abstract Background In hospitalised patients with diarrhoea a positive campylobacter stool Polymerase Chain Reaction (PCR) test with negative culture results as well as Enteropathogenic Escherichia coli (EPEC) positive stool PCRs, challenges the clinician and may lead the unexperienced clinician astray. The aim of the study was to elucidate the clinical significance of positive Campylobacter and/or EPEC test results in hospitalised patients with diarrhoea. Methods We conducted a retrospective case-case study. Case groups with 1) EPEC only and 2) EPEC in combination with any other pathogen in the PCR multiplex array, 3) PCR positive/culture negative Campylobacter, and 4) PCR positive/culture positive Campylobacter were compared. Medical records were reviewed and cases classified according to pre-specified clinical criteria as infectious gastroenteritis or non-infectious causes for diarrhoea. We analyzed the association between laboratory findings (the 4 subgroups) and the pre-specified clinical classification. We further sequenced culture negative campylobacter samples and tested EPEC for bundle forming pilus A (bfpA) gene, distinguishing typical from atypical EPEC. Results A total of 291 patients were included, 169 were PCR positive for Campylobacter and 122 for EPEC. For both pathogens, co-infections were more common in culture negative/PCR positive samples than in culture positive samples. Clinical characteristics differed significantly in and between groups. Campylobacter culture positive patients had very high prevalence of characteristics of acute infectious gastroenteritis, whereas patients with PCR positive test results only often had an alternative explanation for their diarrhoea. Culture positives were almost exclusively C. jejuni/coli, whereas in culture negatives, constituting a third of the total PCR positives, C. concisus was the most frequent species. The vast majority of EPEC only positives had documented non-infectious factors that could explain diarrhoea. The EPEC co-infected group mimicked the culture positive campylobacter group, with most patients fulfilling the infectious gastroenteritis criteria. Conclusions In hospitalised patients, positive PCR results for campylobacter and EPEC should be interpreted in a clinical context after evaluation of non-infectious diarrhoea associated conditions, and cannot be used as a stand-alone diagnostic tool.…

Wassenaar, Annelies; Schoonhoven, Lisette; Devlin, John W.; van Haren, Frank M. P.; Slooter, Arjen J. C.; Jorens, Philippe G.; van der Jagt, Mathieu; Simons, Koen S.; Egerod, Ingrid; Burry, Lisa D.; Beishuizen, Albertus; Matos, Joaquim; Donders, A. Rogier T.; Pickkers, Peter; van den Boogaard, Mark

Objectives: To externally validate two delirium prediction models (early prediction model for ICU delirium and recalibrated prediction model for ICU delirium) using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. Design: Prospective, multinational cohort study. Setting: Eleven ICUs from seven countries in three continents. Patients: Consecutive, delirium-free adults admitted to the ICU for greater than or equal to 6 hours in whom delirium could be reliably assessed. Interventions: None. Measurements and Main Results: The predictors included in each model were collected at the time of ICU admission (early prediction model for ICU delirium) or within 24 hours of ICU admission (recalibrated prediction model for ICU delirium). Delirium was assessed using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. Discrimination was determined using the area under the receiver operating characteristic curve. The predictive performance was determined for the Confusion Assessment Method-ICU and Intensive Care Delirium Screening Checklist cohort, and compared with both prediction models’ original reported performance. A total of 1,286 Confusion Assessment Method-ICU–assessed patients and 892 Intensive Care Delirium Screening Checklist–assessed patients were included. Compared with the area under the receiver operating characteristic curve of 0.75 (95% CI, 0.71–0.79) in the original study, the area under the receiver operating characteristic curve of the early prediction model for ICU delirium was 0.67 (95% CI, 0.64–0.71) for delirium as assessed using the Confusion Assessment Method-ICU and 0.70 (95% CI, 0.66–0.74) using the Intensive Care Delirium Screening Checklist. Compared with the original area under the receiver operating characteristic curve of 0.77 (95% CI, 0.74–0.79), the area under the receiver operating characteristic curve of the recalibrated prediction model for ICU delirium was 0.75 (95% CI, 0.72–0.78) for assessing delirium using the Confusion Assessment Method-ICU and 0.71 (95% CI, 0.67–0.75) using the Intensive Care Delirium Screening Checklist. Conclusions: Both the early prediction model for ICU delirium and recalibrated prediction model for ICU delirium are externally validated using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. Per delirium prediction model, both assessment tools showed a similar moderate-to-good statistical performance. These results support the use of either the early prediction model for ICU delirium or recalibrated prediction model for ICU delirium in ICUs around the world regardless of whether delirium is evaluated with the Confusion Assessment Method-ICU or Intensive Care Delirium Screening Checklist. This work was performed at the Radboud University Medical Center, Tufts Medical Center, The Canberra Hospital, Antwerp University Hospital, Erasmus Medical Center, Jeroen Bosch Ziekenhuis, Rigshospitalet, Mount Sinai Hospital, Medisch Spectrum Twente, Hospital Espírito Santo, and University Medical Centre Utrecht. Drs. Wassenaar, Schoonhoven, Donders, Pickkers, and van den Boogaard contributed to study concept and design. Drs. Wassenaar, Devlin, and van Haren, Slooter, Jorens, van der Jagt, Simons, Egerod, Burry, and Beishuizen, and Mr. Matos contributed to acquisition of data. Drs. Wassenaar, Donders, and van den Boogaard contributed to statistical analysis. Drs. Wassenaar, Schoonhoven, Donders, Pickkers, and van den Boogaard contributed to analysis and interpretation of data. Dr. Wassenaar contributed to drafting of the article. Drs. Schoonhoven, Devlin, and van Haren, Slooter, Jorens, van der Jagt, Simons, Egerod, Burry, and Beishuizen, Mr. Matos, and Drs. Donders, Pickkers, and van den Boogaard contributed to critical revision of the article for important intellectual content. Drs. Schoonhoven, Pickkers, and van den Boogaard contributed to study supervision. All authors read and approved the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Pickkers received funding from AM-Pharma, Adrenomed, Exponential Biotherapies, and Baxter Consultation (speaking fee). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mark.vandenboogaard@radboudumc.nl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kyriacou DN.

Sepsis is estimated to affect more than 30 million people and cause an estimated 6 million deaths worldwide every year. Although new medical treatments are continually being proposed and tested, the greatest reduction in sepsis-related deaths over the past few decades has come from the early recognition of this syndrome and rapid treatment with intravenous antibiotics and crystalloid fluid resuscitation. These important components of sepsis management have been bundled with other critical care interventions and laboratory tests as recommended in the Surviving Sepsis Campaign guidelines. However, aggressive sepsis management according to these guidelines often is not implemented in hospital settings, resulting in higher than necessary mortality and morbidity rates.

Kuehn B, Kuehn B.

Increasing alcohol use worldwide threatens to derail the World Health Organization’s (WHO’s) goal of cutting alcohol use by 10% by 2025, according to a study in The Lancet.

Abstract Background Elevated rates of Hepatitis C Virus (HCV) infection have been reported in epidemiological studies with people who used illicit drugs (PWUIDs) in different Brazilian regions. In Brazil’s Amazon region, studies have already identified the common use of illicit drugs among adolescents and the high prevalence of HCV infections among PWUIDs. However, all studies done with PWUIDs were conducted with small samples and within limited geographic coverage. This study determined the prevalence and risk factors for HCV infection in PWUIDs in the Amazon region, northern Brazil, as well as estimating the prevalence and factors associated with the HCV spontaneous clearance (HSC). Methods This cross-sectional study accessed 1666 PWUIDs from multiple municipalities of the Amazon region. Socio-demographic, economic, drug use and health-related information were collected through interviews. Blood samples collected were tested for the presence of anti-HCV antibodies and RNA-HCV. HCV genotypes were identified by real-time polymerase chain reaction (PCR). Logistic regressions were run to identify factors independently associated with HCV infection status and HSC. Results In total, 577 (34.6%) featured HCV antibodies, of which 384 (23.1%) had active HCV infection and 193 (11.6%) indicated HSC. Genotypes 1 (80.2%) and 3 (18.8%) were detected. HCV infection status was associated with the length of illicit drug use history, factors related to parenteral and sexual transmission, and factors of socio-economic marginalization leading to potential risk activities for HCV. HSC was associated with the ethnic (including indigenous) background of participants. Conclusions High levels of HCV infection were detected in PWUIDs. Genotype 1 was predominant. Intense use of illicit drugs, unprotected sexual intercourse, high number of sexual partners and social marginalization were associated with all HCV infection. HSC was associated with origin (Amazonian-born) and non-white (e.g., Black or Indigenous) of PWUIDs. These findings emphasize the need for improve HCV prevention and control services and care for PWUIDs in the Brazilian Amazon region.…

Halperin S, Das R, Onorato M, et al.

AbstractBackgroundThis double-blind study assessed immunogenicity, lot consistency, and safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP).MethodsHealthy adults (N = 1197) were randomized 2:2:2:2:1 to receive 1 of 3 consistency lots of rVSVΔG-ZEBOV-GP (2 × 107 plaque-forming units [pfu]), high-dose 1 × 108 pfu, or placebo. Antibody responses pre-/postvaccination (28 days, 6 months; in a subset [n = 566], months 12, 18, and 24) were measured. post hoc analysis of risk factors associated with arthritis following vaccination was performed.ResultsZEBOV-GP enzyme-linked immunosorbent assay (ELISA) geometric mean titers (GMTs) increased postvaccination in all rVSVΔG-ZEBOV-GP groups by 28 days (>58-fold) and persisted through 24 months. The 3 manufacturing lots demonstrated equivalent immunogenicity at 28 days. Neutralizing antibody GMTs increased by 28 days in all rVSVΔG-ZEBOV-GP groups, peaking at 18 months with no decrease through 24 months. At 28 days, ≥94% of vaccine recipients seroresponded (ZEBOV-GP ELISA, ≥2-fold increase, titer ≥200 EU/mL), with responses persisting at 24 months in ≥91%. Female sex and a history of arthritis were identified as potential risk factors for the development of arthritis postvaccination.ConclusionsImmune responses to rVSVΔG-ZEBOV-GP persisted to 24 months. Immunogenicity and safety results support continued rVSVΔG-ZEBOV-GP development.Clinical Trials RegistrationNCT02503202.

In the Original Investigation entitled “Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial,” published in the February 19, 2019, issue of JAMA, an incorrect conversion factor of 2.4 was used to convert fentanyl to morphine equivalents. The correct conversion factor is 100. Data related to postoperative morphine equivalents administered, as reported in the Abstract, Results section of the main article text, Tables 2 and 3, and eFigures 1 and 2 in Supplement 2, were recalculated using the correct conversion factor. This article was corrected online.

Abstract Background Malnutrition and diabetes are risk factors for active tuberculosis (TB), possible risk factors for latent TB infection (LTBI), and may interact to alter their effect on these outcomes. Studies to date have not investigated this interaction. Methods We enrolled 919 newly diagnosed active TB patients and 1113 household contacts at Primary Health Centres in Puducherry and Tamil Nadu, India from 2014 to 2018. In cross-sectional analyses, we used generalized estimating equations to measure additive and multiplicative interaction of body mass index (BMI) and diabetes on two outcomes, active TB and LTBI. Results Among overweight or obese adults, active TB prevalence was 12-times higher in diabetic compared to non-diabetic participants, 2.5-times higher among normal weight adults, and no different among underweight adults (P for interaction

Wanek MR.

To the Editor The DEXACET trial found a decreased incidence of postoperative delirium in older patients after cardiac surgery who received intravenous (IV) acetaminophen vs placebo combined with propofol or dexmedetomidine. Dr Subramaniam and colleagues suggested that the difference in the primary outcome, incidence of delirium, may have been driven in part by reduction in opioid consumption in the acetaminophen group compared with the placebo group. The reduction in opioid requirements must therefore be carefully examined.

Subramaniam B, Shankar P, Mueller A.

In Reply We agree with Dr Wanek that the fentanyl conversion factor for morphine equivalents was incorrect. A conversion factor of 2.4 was used per current recommendations for conversion of fentanyl transdermal patch dosage in micrograms per hour to morphine equivalents in milligrams per day. Cardiac surgical patients in this trial received IV fentanyl; therefore, the correct conversion factor for fentanyl in an opioid-naive patient is 100 (ie, 100 µg of fentanyl = 10 mg of morphine). We recalculated additional postoperative analgesic requirements as the sum of (fentanyl dose × 100) + (hydromorphone dose × 4) + morphine dose + (oxycodone dose × 1.5) morphine milligram equivalents. In the original article, the median opioid dose was 322.5 µg in the acetaminophen groups and 405.3 µg in the placebo groups (difference, −83 µg; 95% CI, −154 to −14 µg; P = .02). Using the revised formula, the acetaminophen groups still received a lower opioid dose in the first 48 hours postoperatively compared with the placebo groups (median, 10 082.5 µg vs 12 609.0 µg; difference, −2530.0 µg; 95% CI, −5064 to −22 µg; P = .03), which was statistically significant. The article has been corrected online.