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Xenon Ventilation During Therapeutic Hypothermia in Neonatal Encephalopathy: A Feasibility Study

Hypothermia treatment of neonatal encephalopathy reduces death and disability from 66% to 50%; additional neuroprotective therapies are needed. We previously found in animal models that adding 50% xenon to the breathing gas during cooling doubled neuroprotection.

This clinical feasibility study used 50% xenon for 3 to 18 hours in 14 cooled infants with cardiovascular, respiratory, and amplitude-integrated EEG monitoring. This depressed seizures, with no blood pressure reduction. Xenon is ready for randomized clinical trials in newborns. (Read the full article)




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Respiratory Syncytial Virus Prophylaxis in Down Syndrome: A Prospective Cohort Study

Down syndrome is an independent risk factor for severe respiratory syncytial virus infection and subsequent hospitalization.

This observational study suggests that immunoprophylaxis may reduce respiratory syncytial virus-related hospitalization by 3.6-fold (95% confidence interval, 1.5–8.7) in children with Down syndrome overall. (Read the full article)




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Neurobehavioral Comorbidities in Children With Active Epilepsy: A Population-Based Study

In addition to seizures, school-aged children with epilepsy can have coexisting cognitive and behavioral difficulties, but the spectrum and prevalence of such difficulties are uncertain.

This study provides population-based data on the prevalence of common comorbid cognitive impairments and factors associated with such diagnoses in school-aged children with "active" epilepsy. (Read the full article)




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Firearm Homicide and Other Causes of Death in Delinquents: A 16-Year Prospective Study

Homicide is the third leading cause of mortality in general population youth aged 15 to 29 years. Groups at greatest risk for early violent death (racial/ethnic minorities, males, poor persons, and urban youth) are overrepresented in the juvenile justice system.

We examined rates of and risk factors for firearm homicide and other causes of death in delinquents 16 years after detention. Our study analyzes gender differences; compares Hispanics, African Americans, and non-Hispanic whites; and includes a representative sample of delinquents. (Read the full article)




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Autism Spectrum Disorders and Race, Ethnicity, and Nativity: A Population-Based Study

Autism prevalence is reported to be highest among non-Hispanic white children, lower in Hispanic and African American/black children, and highly variable in Asian/Pacific Islanders. More comorbid intellectual disability and delays in expressive language have been observed among Hispanic and African American children.

Maternal nativity is a risk factor for childhood autism in US populations. We observed higher risk of severe autism phenotypes in children of foreign-born black, Central/South American, Filipino, and Vietnamese mothers and US-born African Americans and Hispanics compared with US-born whites. (Read the full article)




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Early-Onset Basal Cell Carcinoma and Indoor Tanning: A Population-Based Study

Indoor tanning has gained widespread popularity among adolescents and young adults. Incidence rates of early-onset basal cell carcinoma also appear to be rising. Scant evidence exists on the impacts of early exposure and whether it leads to early occurrence of this malignancy.

In a US population-based study, indoor tanning was associated with an elevated risk of basal cell carcinomas occurring at or before the age of 50 years, with an increasing trend in risk with younger age at exposure among adolescents and young adults. (Read the full article)




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HIV and Child Mental Health: A Case-Control Study in Rwanda

Research has shown that HIV-affected children face considerable threats to health and mental health. Few studies have investigated the effects of HIV on the health and well-being of HIV-negative children living with HIV-positive caregivers.

By comparing the prevalence of mental health problems and protective and risk factors among HIV-positive, HIV-affected, and HIV-unaffected children in Rwanda, this study demonstrates that the mental health of HIV-affected children requires policy and programmatic responses comparable to HIV-positive children. (Read the full article)




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A Multicenter Cohort Study of Treatments and Hospital Outcomes in Neonatal Abstinence Syndrome

Neonatal narcotic abstinence syndrome (NAS) has become more prevalent in the United States. There is no strong evidence base for NAS treatment and thus no consensus regarding NAS management, including the best treatment drug or best taper strategy.

This study demonstrates that regardless of the initial treatment opioid chosen, use of a standard treatment protocol with stringent weaning guidelines reduces duration of opioid exposure and length of hospital stay for infants with NAS. (Read the full article)




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Mode of Obstetrical Delivery and Type 1 Diabetes: A Sibling Design Study

Several studies have revealed an association between cesarean section (CS) and childhood type 1 diabetes. Most of these studies lacked important information on indication for CS and induction of labor. It is unknown whether the reported associations are causal.

Using a cohort of 2.6 million children we found an association between elective CS and type 1 diabetes. The sibling analysis suggested the association is not causal. The findings are crucial evidence to advise women on mode of delivery choice. (Read the full article)




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Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

For newborn infants, extreme hyperbilirubinemia (≥24.5 mg/dL) is associated with risk for severe bilirubin encephalopathy. The causal factor of extreme hyperbilirubinemia is often not established. The genotype of Gilbert syndrome, the UGT1A1*28 allele, is considered a potential risk factor.

The UGT1A1*28 allele was not associated with risk for developing extreme hyperbilirubinemia. (Read the full article)




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Missed Opportunities for HPV Vaccination in Adolescent Girls: A Qualitative Study

Rates of human papillomavirus (HPV) vaccination lag behind other adolescent vaccines. Research indicates that provider recommendation is the key to improving HPV vaccination rates and that most adolescents who are unvaccinated received other vaccines, indicating missed opportunities for HPV vaccination.

This study explores in-depth the content of provider–patient conversations that either create or prevent opportunities for HPV vaccination. Effective and ineffective conversations are presented with the goal of providing practical tools to improve communication regarding HPV vaccines. (Read the full article)




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Long-term Study of a Quadrivalent Human Papillomavirus Vaccine

The short-term immunogenicity and safety of a HPV4 vaccine have been previously evaluated in preadolescents and adolescents. To date, no long-term studies of the safety, effectiveness, and immunogenicity of the HPV4 vaccine have been reported in this age group.

The HPV4 vaccine administered to adolescents demonstrated durability in clinically effective protection and sustained antibody titers over 8 years. These data, along with extensive postapproval safety surveillance data, should help reinforce national recommendations for HPV vaccination of preadolescents and adolescents. (Read the full article)




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ADHD, Stimulant Treatment, and Growth: A Longitudinal Study

Stimulant medications are indicated for treatment of childhood attention-deficit/hyperactivity disorder (ADHD), but there is concern that stimulants may negatively affect growth. However, no longitudinal, population-based studies have examined height into adulthood for childhood ADHD cases.

This longitudinal, population-based study shows that neither childhood ADHD itself nor treatment with stimulants is associated with significant deficits in height into adulthood. (Read the full article)




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Bullying and Parasomnias: A Longitudinal Cohort Study

Being bullied can lead to adverse physical and mental health outcomes. Individuals who experience a sudden traumatic event often have short-term disturbances in their sleep patterns. Ongoing trauma may result in extended periods of sleep disruption.

Being bullied in elementary school predicts parasomnias, such as nightmares and night terrors, years later. General practitioners, pediatricians, parents, and teachers may consider parasomnias as potential signs of being bullied. (Read the full article)




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Sibling Bullying and Risk of Depression, Anxiety, and Self-Harm: A Prospective Cohort Study

Recent reviews suggest that children bullied by siblings are at increased risk of internalizing symptoms. It is not known whether being bullied by a sibling increases risk of psychiatric disorders such as depression, anxiety, and self-harm.

Using a large, community-based birth cohort, we found that being bullied by a sibling is prospectively associated with a doubling in the odds of both depression and self-harm at 18 years in young adults. (Read the full article)




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Parental Tdap Boosters and Infant Pertussis: A Case-Control Study

Parental reduced antigen diphtheria-tetanus-acellular pertussis (Tdap) vaccination is difficult to implement, and empirical data on its impact is limited to a single hospital-based study in Texas, which found no reduction in infant pertussis hospitalization.

In New South Wales, Australia, a case-control study found both parents receiving Tdap ≥4 weeks before disease onset was associated with a significant reduction in risk of early infant pertussis and suggestive of persistent protection in subsequent pregnancies. (Read the full article)




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Functional Status in Children With ADHD at Age 6-8: A Controlled Community Study

Children who have attention-deficit/hyperactivity disorder (ADHD) attending clinical services have poorer outcomes in adolescence on a range of measures. However, it is unknown how early in development these impairments appear, particularly for community-ascertained samples.

At age 6 to 8 years, children in the community with ADHD have significantly poorer mental health, academic performance and social function compared with control children. Children who have impairing ADHD symptoms should be referred early for assessment and intervention. (Read the full article)




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Implementation Methods for Delivery Room Management: A Quality Improvement Comparison Study

Quality improvement (QI) studies generally do not account for concurrent trends of improvement and it is difficult to distinguish the impact of a multihospital collaborative QI project without a contemporary control group.

A multihospital collaborative QI model led to greater declines in hypothermia and invasive ventilation rates in the delivery room compared with an individual NICU QI model and NICUs that did not participate in formal QI activities. (Read the full article)




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A Randomized Trial on Screening for Social Determinants of Health: the iScreen Study

Despite growing interest around clinical screening for health-related social and environmental risk factors, little evidence exists regarding screening formats that maximize disclosure of psychosocial information.

This study compares psychosocial and socioeconomic adversity disclosure rates in face-to-face interviews versus electronic formats in a large, urban pediatric emergency department. (Read the full article)




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Changes in Obesity Between Fifth and Tenth Grades: A Longitudinal Study in Three Metropolitan Areas

Obesity among youth can have immediate health effects as well as longer-term consequences during adulthood. Overweight/obese children and adolescents are much more likely than normal-weight children to become overweight/obese adults.

This large, multisite longitudinal study examines patterns of exit from and entry into obesity between childhood and adolescence. Socioeconomic factors, body image, television habits, and parental obesity were important predictors of whether children remained obese or became obese. (Read the full article)




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Trends in Infant Bedding Use: National Infant Sleep Position Study, 1993-2010

The American Academy of Pediatrics has identified bedding such as pillows, blankets, and quilts as potentially hazardous for the infant sleep environment. Bedding use is a modifiable risk factor for sudden infant death syndrome and unintentional sleep-related suffocation.

Reported bedding use over or under the infant for infant sleep substantially declined from 1993 to 2010. However, about one-half of US infants are still placed to sleep with potentially hazardous bedding despite recommendations against this practice. (Read the full article)




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Regional Variation in Antenatal Corticosteroid Use: A Network-Level Quality Improvement Study

Application of antenatal corticosteroids to mothers before delivery is highly beneficial to very low birth weight infants. Yet despite widespread quality improvement efforts, many eligible infants fail to receive this therapy.

We demonstrate improvement in antenatal corticosteroid use during the study period. However, significant regional variation persists, which network-level quality improvement efforts might help eliminate. (Read the full article)




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Childhood Behavior Problems and Age at First Sexual Intercourse: A Prospective Birth Cohort Study

Early first sexual intercourse (FSI) is a risk factor for unplanned teenage pregnancy, sexually transmitted infection, and adverse health outcomes in adolescence and into adulthood. In girls, externalizing behaviors are more strongly associated with earlier FSI than internalizing behaviors.

Externalizing behavior from as early as 5 in boys and 10 in girls is a significant risk factor for earlier age at FSI. Internalizing behavior at ages 8 and 10 was associated with early FSI for boys but not girls. (Read the full article)




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Medication-Related Emergency Department Visits in Pediatrics: a Prospective Observational Study

In adults, adverse drug events account for 5% to 25% of all hospital admissions and 12% of emergency department (ED) visits of which 50% to 70% are preventable. There remains a significant gap in our understanding of the magnitude and impact of medication-related ED visits in pediatrics.

This study is the largest and most rigorous study performed evaluating the impact of medication-related visits to the ED in pediatrics and provides important information regarding the magnitude of this problem in our health care system. (Read the full article)




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Medical Augmentation of Labor and the Risk of ADHD in Offspring: A Population-Based Study

Using large nationwide registers, we were unable to detect any association between augmentation of labor and ADHD in offspring. Our findings do not support a causal role of perinatal exposure to oxytocin during delivery on the development of ADHD. (Read the full article)




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Moisture Damage and Asthma: A Birth Cohort Study

Moisture damage and mold increase the risk of asthma and asthmatic symptoms. However, the location of the damage, or the specific group of children who are at greater risk of asthma, is rarely taken into account.

Inspector-observed moisture damage or mold in the child’s bedroom, living room, or kitchen increased the risk of asthma and persistent asthma during a 6-year follow-up. Atopic children may be more susceptible to the effects of moisture damage and mold. (Read the full article)




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Epidemiology of Pediatric Herpes Zoster After Varicella Infection: A Population-Based Study

This is the first population-based study regarding the epidemiologic characteristics of pediatric zoster among only those who had contracted varicella.

The herpes zoster (HZ) incidence among only children with varicella infection is higher than previously reported. The HZ incidence increased for children contracting varicella aged <2 years. After a vaccination program, the HZ risk increased for those contracting varicella aged ≥2 years. (Read the full article)




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Late Preterm Birth and Neurocognitive Performance in Late Adulthood: A Birth Cohort Study

More than 70% of all preterm deliveries are late preterm (34–36 weeks of gestation). Existing evidence suggests that compared with those born at term, those born late preterm score lower on neurocognitive tests in childhood and young adulthood.

The effect of late preterm birth on neurocognitive performance persists up to late adulthood, especially among those who have only a basic or upper secondary level of education. Late preterm birth is also associated with a risk of memory impairments. (Read the full article)




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Pneumonia in Childhood and Impaired Lung Function in Adults: A Longitudinal Study

Early-life lower respiratory illnesses, including pneumonia, are associated with increased prevalence of asthma and diminished lung function in children. Whether early-life pneumonia is associated with subsequent impaired lung function and asthma in adults is not yet clear.

This is the first article providing strong data for an association between early-life pneumonia in an outpatient setting and airflow limitation and asthma into adulthood, supporting the hypothesis of the early-life origins of chronic obstructive pulmonary disease. (Read the full article)




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Comorbidity of Physical and Mental Disorders in the Neurodevelopmental Genomics Cohort Study

Although there is evidence regarding comorbidity of physical and mental disorders from clinical samples of specific disorders and treatment registries, there is limited evidence from systematic samples of youth with comprehensive information on the full range of mental and physical disorders.

This report is the first study to investigate the specificity of associations between a broad range of mental and physical conditions by using a large, systematically obtained pediatric sample with enriched information from electronic medical records and direct interviews. (Read the full article)




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Mortality After Burn Injury in Children: A 33-year Population-Based Study

Burns are a leading cause of pediatric emergency department visits and hospitalizations and are often associated with significant long-term physical and psychological consequences and long-term medical and nursing treatments. Little is known of the long-term impacts of burns on mortality.

Children with burns had a 1.6 times greater rate of long-term mortality than a matched population-based cohort of children with no injury. Total mortality burden based on in-hospital deaths alone underestimates the true burden from both minor and severe burns. (Read the full article)




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Pediatric Palliative Care and Inpatient Hospital Costs: A Longitudinal Cohort Study

Pediatric palliative care (PPC) improves the quality of life for children with life-limiting illness and their families. The association between PPC and health care costs is unclear and has not been studied over time.

PPC recipients were more medically complex. Receipt of PPC was associated with lower costs when death was near but with greater costs among survivors. When controlling for medical complexity, costs did not differ significantly according to receipt of PPC. (Read the full article)




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Executive Function in Adolescents Born <1000 g or <28 Weeks: A Prospective Cohort Study

Preterm children often experience poor executive function (EF; skills underpinning adaptive, goal-directed behavior, and essential for positive academic, occupational, and social outcomes). EF matures across adolescence, but the nature and course of EF deficits for preterm adolescents is not well-described.

Extremely preterm/extremely low birthweight adolescents demonstrated small-to-medium deficits across multiple EF domains compared with normal birthweight controls. Preterm children improved on some EF aspects from age 8 to late adolescence relative to controls, but not on parent-rated behavioral EF. (Read the full article)




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Identifying Priorities for Mental Health Interventions in War-Affected Youth: A Longitudinal Study

War-affected youth often suffer from multiple co-occurring mental health problems. The relationship of these conditions to later mental health has yet to be thoroughly investigated. There is a need to explore potential targets for mental health interventions.

After controlling for preexisting conditions and contemporary confounders, internalizing (depression and anxiety) remained the major predictor of future mental health symptoms (internalizing symptoms, prosocial attitudes/behaviors, and posttraumatic stress symptoms). Interventions targeting internalizing in war-affected youth hold promise. (Read the full article)




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Antibiotic Exposure and Juvenile Idiopathic Arthritis: A Case-Control Study

The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. A recent study suggested a link between antibiotics and JIA but did not examine the potential for confounding from infections or the role of antibiotic timing.

Antibiotics were associated with newly diagnosed JIA in a dose- and time-dependent manner after adjusting for infection and other confounders. Antibiotics may play a role in the pathogenesis of JIA. (Read the full article)




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Suicide Attempts and Childhood Maltreatment Among Street Youth: A Prospective Cohort Study

Street youth demonstrate elevated mortality compared with the general adolescent and young adult population. Suicide is a leading cause of death among street youth. Many street youth have experienced childhood maltreatment, including abuse and neglect.

In this prospective cohort of street youth, self-reported attempted suicide and history of childhood maltreatment were common. Individuals who experienced childhood physical abuse, emotional abuse, or emotional neglect were at highest risk of attempting suicide. (Read the full article)




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Implementation of a Neonatal Abstinence Syndrome Weaning Protocol: A Multicenter Cohort Study

Use of a standard treatment protocol with stringent weaning guidelines for infants with neonatal abstinence syndrome supports improved outcomes including shorter duration of opioid exposure and length of hospital stay.

We demonstrate generalizability of a protocol-driven weaning strategy for improvement in hospital outcomes for neonatal abstinence syndrome. After adoption, adherent protocol-adopting centers improved outcomes and eliminated differences in outcomes compared with centers with preexisting stringent weaning protocols. (Read the full article)




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Use of a Metronome in Cardiopulmonary Resuscitation: A Simulation Study

The frequency of cardiac arrest is significantly lower in children than in adults, rendering the delivery of high-quality cardiopulmonary resuscitation more difficult. Metronome-based studies in adults showed improvement in adequate compression rate, with a detrimental effect on the depth of chest compressions.

This is the first pediatric study to confirm that the use of a metronome during cardiopulmonary resuscitation significantly improves the delivery of adequate rate without affecting the compression depth. This effect was more prominent among medical students and pediatric residents and fellows than nurses. (Read the full article)




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Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study

Strictly-defined pediatric bipolar I disorder (BP-I) is a serious condition. Although lithium is a benchmark treatment and has shown effectiveness in adults for decades, no definitive efficacy or long-term safety studies had been performed in pediatric patients with BP-I.

This study provides evidence to support the efficacy of lithium in the acute treatment of youths with BP-I who are currently in a manic or mixed state. Lithium had an adverse effect profile that was acceptable for most patients. (Read the full article)




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National Study Bolsters Case for Teaching 'Growth Mindset'

A national study of nearly 12,500 9th graders finds that two sessions of a 25-minute exercise on “growth mindset” can boost students’ grades and their willingness to take on challenging classes.




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Study: Male Teachers Are More Likely to Leave a School With a Female Principal

Men were also more likely to request a transfer to a school with a male principal.




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Study: Digital Summer Learning Boosts Achievement

The report suggests programs delivering instruction through multiple media platforms can lead to significant improvement in students' mathematics, numeracy, and phonics skills.




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UEFA injury study

We find out how UEFA has helped clubs to learn more about injuries with a groundbreaking study




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No, Mentoring a Student-Teacher Won't Hurt Your Evaluation Score, Study Suggests

Mentoring a student-teacher won't hurt a teacher's district evaluation score—in fact, it might even give it a boost, according to a working study.




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Study reveals important flowering plants for city-dwelling honey bees

Trees, shrubs and woody vines are among the top food sources for honey bees in urban environments, according to an international team of researchers. By using honey bees housed in rooftop apiaries in Philadelphia, the researchers identified the plant species from which the honey bees collected most of their food, and tracked how these food resources changed from spring to fall. The findings may be useful to homeowners, beekeepers and urban land managers who wish to sustain honey bees and other bee and pollinator species.




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Malaria risk is highest in early evening, study finds

Wide-scale use of insecticide-treated bed nets has led to substantial declines in global incidences of malaria in recent years. As a result, mosquitos have been shifting their biting times to earlier in the evening and later in the morning. In a new study, an international team of researchers has found that mosquitoes are most likely to transmit malaria in the early evening, when people are exposed, then at midnight, when people are protected by bed nets, or in the morning. The findings may have implications for malaria prevention initiatives.




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Comparison of Cefepime/Cefpirome and Carbapenem Therapy for Acinetobacter Bloodstream Infection: A Multicentre Study [Clinical Therapeutics]

Carbapenems are currently the preferred agents for the treatment of serious Acinetobacter infections. However, whether cefepime/cefpirome can be used to treat Acinetobacter bloodstream infection (BSI) if it is active against the causative pathogens is not clear. This study aimed to compare the efficacy of cefepime/cefpirome and carbapenem monotherapy in patients with Acinetobacter BSI. The population included 360 patients with monomicrobial Acinetobacter BSI receiving appropriate antimicrobial therapy admitted to four medical centres in Taiwan in 2012–2017. The predictors of 30-day mortality were determined by Cox regression analysis. The overall 30-day mortality rate in the appropriate antibiotic treatment group was 25.0% (90/360 patients), respectively. The crude 30-day mortality rates for cefepime/cefpirome and carbapenem therapy were 11.5% (7/61 patients) and 26.3% (21/80 patients), respectively. The patients receiving cefepime/cefpirome/carbapenem therapy were infected by Acinetobacter nosocomialis (51.8%), A. baumannii (18.4%) and A. pittii (12.1%). After adjusting for age, Sequential Organ Failure Assessment (SOFA) score, invasive procedures, and underlying diseases, cefepime/cefpirome therapy was not independently associated with a higher or lower 30-day mortality compared to the carbapenem therapy. SOFA score (hazard ratio [HR], 1.324; 95% confidence interval [CI], 1.137–1.543; P < 0.001) and neutropenia (HR, 7.060; 95% CI, 1.607–31.019; P = 0.010) were independent risk factors for 30-day mortality of patients receiving cefepime/cefpirome or carbapenem monotherapy. The incidence density of 30-day mortality for cefepime/cefpirome versus carbapenem therapy was 0.40% versus 1.04%. The therapeutic response of cefepime/cefpirome therapy was comparable to that of carbapenems among patients with Acinetobacter BSI receiving appropriate antimicrobial therapy.




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Evaluation of the effect of contezolid (MRX-I) on the corrected QTc interval: a randomized, double-blind, placebo- and positive-controlled crossover study in healthy Chinese volunteers [Clinical Therapeutics]

Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections (cSSTI) caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1600 mg) dose, placebo, and oral moxifloxacin 400 mg in 4 separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time-point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (QTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for QTc were slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 hours postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 with having a lower confidence bound ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and QTcF interval with a slope of 0.227 ms per mg/L (90% CI: 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose.




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In vitro and in vivo study on the synergistic effect of minocycline and azoles against pathogenic fungi [Susceptibility]

In vitro and in vivo interactions of minocycline and azoles including itraconazole, voriconazole, and posaconazole against filamentous pathogenic fungi were investigated. A total of 56 clinical isolates were studied in vitro via broth microdilution checkerboard technique, including 20 strains of Aspergillus fumigatus, 7 strains of A. flavus, 16 strains of Exophiala dermatitidis, 10 strains of Fusarium solani and 3 strain s of F. oxysporum. The results revealed that minocycline individually did not exhibit any significant antifungal activity against all tested strains. However, favorable synergy of minocycline with itraconazole, voriconazole, or posaconazole were observed against 34 (61%), 28 (50%), and 38 (69%) isolates, respectively, including azole resistant A. fumigatus and Fusarium spp. with inherently high MICs of azoles. Synergistic combinations resulted in 4 fold to 16-fold reduction of effective MICs of minocycline and azoles. No antagonism was observed. In vivo effect of minocycline-azole combinations were evaluated by survival assay in Galleria mellonella model infected with E. dermatitidis strain BMU00034, F. solani strain FS9, A. fumigatus strain AF293, AFR1 and AFR2 . Minocycline acted synergistically with azoles and significantly increased larvae survival in all isolates (P<0.001), including azole resistant A. fumigatus and azole-inactive Fusarium spp.. In conclusion, the results suggested that minocycline combined with azoles may help to enhance the antifungal susceptibilities of azoles against pathogenic fungi and had the potential to overcome azole resistance issues.




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A genotype-phenotype correlation study of SHV {beta}-lactamases - new insight into SHV resistance profiles [Mechanisms of Resistance]

The SHV β-lactamases (BLs) have undergone strong allele diversification that changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted five positions as relevant for the β-lactamase inhibitor (BLI) resistant (2br) phenotype, 12 as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and two positions were related to solely the narrow spectrum (2b) phenotype. These positions and additional 6 positions described in other studies (including one promoter mutation), were systematically substituted and investigated for their substrate specificities in a BL-free E. coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of the positions 238 and 179 for the 2be phenotype and 69 for the 2br phenotype. The substitutions E240K and E240R, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI-resistance potential of these substitutions. The substitutions M129V, A234G, S271I and R292Q conferred latent resistance to cefotaxime. In addition, 7 positions that were found to be not always associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to a A146V mutant with the 2b phenotype resulted in a highly increased resistance to BLIs, cefepime and ceftaroline but not to 3rd generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin/tazobactam or cefepime to treat different infectious diseases caused by gram-negatives.