Gal Dubnov-Raz

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

BACKGROUND Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each days delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each days delay). INTERPRETATION We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING F Hoffmann-La Roche.

Colchicine poisoning: the dark side of an ancient drug

Introduction. Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. Methods. We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included “colchicine” and “poisoning” or “overdose” or “toxicity” or “intoxication.” Toxicokinetics. Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. Therapeutic and toxic doses. The usual adult oral doses for FMF is 1.2–2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5–0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7–26 mg. Drug interactions. CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy. Mechanisms of toxicity. Colchicines toxicity is an extension of its mechanism of action – binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. Reproductive toxicology and lactation. Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation. Clinical features. Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10–24 h after ingestion – gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion – multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness. Diagnosis. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Management. Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available. Conclusion. Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.

Invasive pediatric Kingella kingae infections: a nationwide collaborative study.

Background: Kingella kingae is a gram-negative coccobacillus, increasingly recognized as an invasive pediatric pathogen. To date, only few small series of invasive K. kingae infections have been published, mostly from single medical centers. A nationwide multicenter study was performed to investigate the epidemiologic, clinical, and laboratory features of children with culture-proven K. kingae infections. Methods: Clinical microbiology laboratories serving all 22 medical centers in Israel were contacted in a search for children aged 0 to 18 years from whom K. kingae was isolated from a normally sterile site, dating from as far back as possible until December 31, 2007. Medical records of identified patients were reviewed using uniform case definitions. Results: A total of 322 episodes of infection were identified in 321 children, of which 96% occurred before the age of 36 months. The annual incidence in children aged <4 years was 9.4 per 100,000. Infections showed a seasonal nadir between February and April. Skeletal system infections occurred in 169 (52.6%) children and included septic arthritis, osteomyelitis, and tenosynovitis. Occult bacteremia occurred in 140 children (43.6%), endocarditis in 8 (2.5%), and pneumonia in 4 (1.2%). With the exception of endocarditis cases, patients usually appeared only mildly ill. About one-quarter of children had a body temperature <38°C, 57.1% had a blood white blood cell count <15,000/mm3, 22.0% had normal C-reactive protein values, and 31.8% had nonelevated erythrocyte sedimentation rate. Conclusions: K. kingae infections usually occur in otherwise healthy children aged 6 to 36 months, mainly causing skeletal system infections and bacteremia, and occasionally endocarditis and pneumonia. Clinical presentation is usually mild, except for endocarditis, necessitating a high index of suspicion.

High prevalence of vitamin d insufficiency in athletes and dancers

Objective: Vitamin D insufficiency is prevalent in various populations worldwide but with scarce data on physically active individuals. Vitamin D is important to athletes, affecting bone mass, immunity, and physical performance. This study evaluated the prevalence of vitamin D insufficiency and deficiency among young athletes and dancers. Design: Cross-sectional study. Setting: Sport medicine clinic. Patients: Data on 98 athletes and dancers (age, 14.7 ± 3.0 years; range, 10-30 years; 53% men), who had undergone screening medical evaluations, were extracted from medical records. Independent Variable: Serum 25(OH)D concentrations. Main Outcome Measures: Serum 25(OH)D concentrations, age, sex, sport discipline, month of blood test, and serum ferritin. Vitamin D insufficiency was defined as serum 25(OH)D concentration <30 ng/mL. Results: Mean serum 25(OH)D concentration was 25.3 ± 8.3 ng/mL. Seventy-three percent of participants were vitamin D insufficient. Prevalence of vitamin D insufficiency was higher among dancers (94%), basketball players (94%), and Tae Kwon Do fighters (67%) and among athletes from indoor versus outdoor sports (80% vs 48%; P = 0.002). 25(OH)D levels adjusted for age and sex correlated with serum ferritin and season. Conclusions: In this study, conducted among young athletes and dancers from various disciplines in a sunny country, a high prevalence of vitamin D insufficiency was identified. A higher rate of vitamin D insufficiency was found among participants who practice indoors, during the winter months, and in the presence of iron depletion. Given the importance of vitamin D to athletes for several reasons, we suggest that athletes and dancers be screened for vitamin D insufficiency and treated as needed.

Invasive Kingella kingae Infections in Children: Clinical and Laboratory Characteristics

OBJECTIVE. Kingella kingae, a Gram-negative coccobacillus, is being increasingly recognized as an invasive pathogen in children, causing mainly bacteremia and arthritis; however, there have been only a few studies on K kingae infections to date, mostly small-scale series. The aim of this study was to report our experience with invasive K kingae infections in children who were hospitalized at a major tertiary medical center in Israel. METHODS. The medical charts of 62 children with proven invasive K kingae infections were reviewed: 42 with positive blood culture results and 20 with positive synovial fluid culture results. RESULTS. Most infections occurred among previously healthy children aged 5 to 22 months. Eighty percent had a mild concurrent illness of the respiratory or gastrointestinal tract. A chronic underlying disease was documented in 19% of the 1- to 15-year-old children with bacteremia. Three patients had persistent bacteremia, identified by 2 positive blood cultures drawn 1 to 4 days apart. Four (10%) patients from the bacteremia group had endocarditis, and 2 required emergency cardiac surgery. Only a mild-to-moderate elevation of serum inflammatory markers was noted except for patients with endocarditis or a prolonged course of arthritis. Patients with bacteremia received a diagnosis significantly later than those with arthritis, with no other between-group differences in age, month of disease onset, and inflammatory marker levels. All K kingae isolates were resistant to vancomycin and clindamycin. CONCLUSIONS. Our large series indicates that invasive K kingae infections occur in previously healthy children, mostly during the first 2 years of life; affected older children usually have an underlying medical condition. The infection generally elicits only a mild inflammatory response unless accompanied by endocarditis. Despite its low virulence, K kingae might cause a life-threatening heart disease that requires emergent, aggressive treatment.

Antenatal Use of Selective Serotonin-Reuptake Inhibitors and QT Interval Prolongation in Newborns

OBJECTIVES. Prolongation of the QT interval is a risk factor for sudden death. Selective serotonin-reuptake inhibitor antidepressants can prolong the QT interval and are widely used by pregnant women. Whether antenatal exposure to selective serotonin-reuptake inhibitor causes QT prolongation in offspring is unknown. The aim of this study was to determine the effect of maternal use of selective serotonin-reuptake inhibitor antidepressants during pregnancy on the QTc interval of the offspring. METHODS. Between January 2000 and December 2005, we collected data on all of the newborns born at a single tertiary care hospital. Electrocardiograms of infants exposed to selective serotonin-reuptake inhibitor antidepressants in utero were compared with those of healthy control newborns matched on gestational age. The tracings were interpreted by a pediatric cardiologist who was unaware of the drug exposure. RESULTS. We identified 52 newborns exposed to selective serotonin-reuptake inhibitor antidepressants in the immediate antepartum period and 52 matched control subjects. The mean QTc was significantly longer in the group of newborns exposed to antidepressants as compared with control subjects (409 ± 42 vs 392 ± 29 milliseconds). Five (10%) newborns exposed to selective serotonin-reuptake inhibitor antidepressants had a markedly prolonged QTc interval (>460 milliseconds) compared with none of the unexposed newborns. The longest QTc interval observed among exposed newborns was 543 milliseconds. All of the drug-associated repolarization abnormalities normalized in subsequent electrocardiographic tracings. CONCLUSIONS. Antepartum use of selective serotonin-reuptake inhibitor antidepressants is associated with QTc interval prolongation in exposed neonates. Additional research using a standardized protocol is needed to determine whether exposure to selective serotonin-reuptake inhibitor antidepressants in late pregnancy is also associated with arrhythmias.

Body Mass Index of Children With Attention-Deficit/Hyperactivity Disorder

An association between overweight and attention-deficit/hyperactivity disorder (ADHD) in children was previously suggested. We examined the prevalence of overweight, anthropometric changes, and the effect of methylphenidate treatment in 275 children with ADHD without neurological comorbidities and in controls. Data were extracted from medical charts, for up to 17 months of follow-up. Height, weight, body mass index, and their z scores did not differ between the ADHD and control groups. Prevalence of overweight and obesity was lower in the ADHD group compared with controls (19% vs 35%, P = .02, and 7% vs 16%, P = .05, respectively). During a follow-up of up to 17 months, no significant changes in height or body mass index z scores were found, including in a subgroup of overweight children. We conclude that compared with local controls, children with ADHD have rates of overweight and obesity that are lower, but that are similar to national estimates. Methylphenidate treatment did not significantly affect height, weight, or overweight status.

Relationship of Hyperactivity/Inattention With Adiposity and Lifestyle Characteristics in Preschool Children

We performed a cross-sectional study in 450 nonreferred preschool children aged 4 to 6 years to assess the association between hyperactivity/inattention with adiposity and lifestyle characteristics. Measurements included scores of hyperactivity/inattention, adiposity, objectively measured physical activity, television viewing, and eating habits. Higher scores of hyperactivity/inattention were associated with lower percentage body fat, higher levels of physical activity, and less time spent in sedentary activity (all P ≤ .01). However, higher scores of hyperactivity/inattention were also associated with more television viewing and less healthy eating habits (all P ≤ .04). Except for some selected eating habits (P ≥ .07), those relationships remained significant after adjustment for age, sex, and sociodemographic confounders. To conclude, higher scores of hyperactivity/inattention are linked to different lifestyle characteristics that may in part contribute to a future development of overweight/obesity. Precise mechanisms explaining these associations and possible preventive approaches should be further investigated.

Physical activity and bone mineral density in adolescents with vitamin D deficiency.

INTRODUCTION Studies have shown that physical activity (PA) is superior to many other environmental factors in determining bone mineral density (BMD), but none has examined the independent relationship between PA and vitamin D status. PURPOSE The aim of this study was to assess the relationship among amount of PA, vitamin D (25(OH)D), and BMD. METHODS A total of 166 female ballet dancers and sedentary adolescents were divided by tertiles of serum levels of 25(OH)D (< 11.3, 11.3-14.9, and > or = 15 ng·mL(-1)). Diet, PA, and menstruation were assessed by questionnaires; BMD was measured in three sites by dual-energy x-ray absorptiometry. RESULTS Across 25(OH)D tertiles, there were no differences in mean participant age, weight, height, PA, calcium and energy intake, BMD, or parathyroid hormone. PA was positively associated with BMD in participants with vitamin D deficiency. Multivariable regression analysis, controlling for age, body mass index, parathyroid hormone, and bone turnover markers, showed that total body, femoral neck, and lumbar spine BMD were all positively related to PA, with regression coefficients increasing as vitamin D levels dropped across tertiles. CONCLUSIONS PA is positively related to BMD in vitamin D-deficient female adolescents and with increasing magnitude as serum vitamin D levels drop. These findings suggest that PA may counteract the detrimental effect of marked vitamin D deficiency on bone mass.

Maternal use of selective serotonin reuptake inhibitors during pregnancy and neonatal bone density

BACKGROUND Selective serotonin reuptake inhibitors (SSRI) are commonly used to treat depression in pregnant women. Several adverse effects of prenatal SSRI exposure on the offspring have been described, including decreased growth. SSRI use by adults decreases bone mineral density, but this effect had not been examined in infants. AIM To examine growth parameters and bone mineral density of infants born to mothers using SSRIs during pregnancy. STUDY DESIGN Anthropometric variables and bone density were compared between 40 newborns exposed to SSRIs in utero, and 40 gestational-age matched control infants. Tibial bone speed of sound, a marker of bone density and strength, was measured using quantitative ultrasound. The difference in bone speed of sound between the two groups was compared using linear models, adjusting for relevant confounders. RESULTS Infants in the SSRI-exposed group were shorter, with a marginal statistical significance (49.3±2.1 vs. 50.1±1.3cm, p=0.07), while mean birth weight did not differ substantially between study groups. Head circumference was significantly smaller in the SSRI group (33.8±1.2 vs 34.4±1.1cm, p=0.005), remaining so even after adjustment for several confounders. No considerable difference was found in the bone speed of sound between SSRI-exposed infants and controls (3011±116 vs. 3029±129m/s). CONCLUSIONS We found no evidence that prenatal SSRI exposure hindered neonatal bone quality, yet a marginally shorter length and a smaller head circumference raise the possibility of an effect on bone growth. We conclude that the effect of SSRIs on fetal bone density seems minimal or absent.