Relationship of Multiplex Molecular Pneumonia Panel Results With Hospital Outcomes and Clinical Variables.

BACKGROUND: Antibiotic treatment decisions in severely ill patients must often be made in the absence of microbiologic results. The recently Food and Drug Administration-cleared BioFire FilmArray Pneumonia Panel (PN) detects 15 bacteria semiquantitatively, 3 atypical pneumonia bacteria, 8 viruses, and 7 antimicrobial resistance markers by multiplex PCR in ~1 hour in the laboratory. Previous reports have shown that the PN Panel bacterial detections are highly accurate, even when routine culture had no growth. METHODS: Consecutive bronchoalveolar lavage and endotracheal specimens submitted for culture between June and September 2018 from 270 patients with sufficient clinical and laboratory data were tested with the PN Panel. Patients were divided into 3 groups: (1) both culture and PN Panel positive, (2) PN Panel positive but culture uninformative (no growth or normal flora), and (3) patients with no PN Panel detections. RESULTS: Groups 1 and 2 had significantly higher maximum temperatures on the day of culture (P = .00036, analysis of variance [ANOVA] with Bonferroni correction), higher levels of an inflammatory response as measured by percent polymorphonuclear leukocytes in bronchoalveolar lavage (P = .00025, ANOVA with Bonferroni correction), and gram stain report of white blood cells, as previously reported [1]. CONCLUSIONS: Both group 1 (culture and PN Panel positive), and group 2 (PN Panel positive but culture uninformative) had higher levels of host response inflammatory responses compared with group 3, which had no targets detected, suggesting that PN Panel detections need to be interpreted in the clinical context, even if cultures are discordant. Depending on laboratory turnaround time, there could be opportunities for improved diagnosis and antibiotic stewardship.

[Digoxin-related leukocytoclastic vasculitis in a very elderly woman: A case report]. / Vascularite leucocytoclasique liée à la digoxine chez une femme très âgée : à propos d'un cas.

Even though digoxin causes many side effects, few cases of skin involvement are recorded in the French Pharmacovigilance Database. We report a case of leukocytoclastic vasculitis (LV) very probably due to digoxin. A 91-year-old woman, hospitalized following a fall, presented cardiac decompensation in a context of rapid atrial fibrillation requiring treatment with digoxin. Eight days later, a rash appeared on her back and trunk. It was neither itchy, nor painful and persisted despite local treatment. There were no other clinical anomalies. After a few days, the rash spread with appearance of bullous lesions, ulcerations and a necrosis on lymphedema of the two legs. Among the complementary examinations, skin biopsy revealed LV with necrosis and subepidermal detachment suggested toxic dermal necrolysis, while direct immunofluorescence was negative. The rash resolved progressively once the digoxin was stopped. The pharmacovigilance department recorded that digoxin was the probable cause. The evidence allowed us to conclude that digoxin was the cause.

Antibiotic failure in a renal transplant patient with Rhodococcus equi infection: an indication for surgical lobectomy.

Rhodococcus equi is an animal pathogen that causes infrequent but challenging infections in immunocompromised individuals, few of which have been described in solid organ transplant recipients. Common clinical presentations include indolent cough, fever, and dyspnea, with necrotizing pneumonia and cavitation. We report a case of a dense right upper lung pneumonia with resultant R. equi bacteremia in a renal transplant recipient. Our patient initially responded to antibiotic treatment with resolution of bacteremia and clinical recovery, followed by interval progression in her right upper lobe consolidation on follow-up computed tomography scans. She underwent lobectomy for definitive therapy with resolution of symptoms. Lobectomy can be utilized in isolated infection after antibiotic failure with excellent clinical outcomes.

Constitutional haploinsufficiency of tumor suppressor genes in mentally retarded patients with microdeletions in 17p13.1.

Chromosome microdeletions or duplications are detected in 10-20% of patients with mental impairment and normal karyotypes. A few cases have been reported of mental impairment with microdeletions comprising tumor suppressor genes. By array-CGH we detected 4 mentally impaired individuals carrying de novo microdeletions sharing an overlapping segment of approximately 180 kb in 17p13.1. This segment encompasses 18 genes, including 3 involved in cancer, namely KCTD11/REN, DLG4/PSD95, and GPS2. Furthermore, in 2 of the patients, the deletions also included TP53, the most frequently inactivated gene in human cancers. The 3 tumor suppressor genes KCTD11, DLG4, and GPS2, in addition to the GABARAP gene, have a known or suspected function in neuronal development and are candidates for causing mental impairment in our patients. Among our 4 patients with deletions in 17p13.1, 3 were part of a Brazilian cohort of 300 mentally retarded individuals, suggesting that this segment may be particularly prone to rearrangements and appears to be an important cause (approximately 1%) of mental retardation. Further, the constitutive deletion of tumor suppressor genes in these patients, particularly TP53, probably confers a significantly increased lifetime risk for cancer and warrants careful oncological surveillance of these patients. Constitutional chromosome deletions containing tumor suppressor genes in patients with mental impairment or congenital abnormalities may represent an important mechanism linking abnormal phenotypes with increased risks of cancer.

The need for mixed-effects modeling with population dichotomous data.

Over the past 25 years sophisticated data analytic techniques have been developed which can lead to improved analyses, but at additional computational cost. In particular, this applies to the approach where interindividual random effects are included in a data analytic model for population pharmacokinetic data, which can often lead to substantially improved estimates of fixed-effect parameters. However, there are also commonly occurring situations, notably with some types of pharmacodynamic data, where such improvement is not realized. This study simulates some simple population dichotomous data, and secondarily, some related continuous data. These data are analyzed using both mixed-effect (ME) models that include interindividual random effects and naive (NA) models that do not include interindividual random effects, and it is seen that use of an ME model does not inevitably lead to gains over use of an NA model. In fact, using maximum likelihood estimation with both types of models, the root mean square estimation errors for fixed effect parameters can actually be larger with an ME model than with the corresponding NA model. Using a form of restricted maximum likelihood estimation with the ME model, the two types of models yield root mean square errors which are comparable, but which still do not suggest that there is always marked advantage in using the ME model.

Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check.

The posterior predictive check (PPC) is a model evaluation tool. It assigns a value (pPPC) to the probability that the value of a given statistic computed from data arising under an analysis model is as or more extreme than the value computed from the real data themselves. If this probability is too small, the analysis model is regarded as invalid for the given statistic. Properties of the PPC for pharmacokinetic (PK) and pharmacodynamic (PD) model evaluation are examined herein for a particularly simple simulation setting: extensive sampling of a single individual's data arising from simple PK/PD and error models. To test the performance characteristics of the PPC, repeatedly, "real" data are simulated and for a variety of statistics, the PPC is applied to an analysis model, which may (null hypothesis) or may not (alternative hypothesis) be identical to the simulation model. Five models are used here: (PK1) mono-exponential with proportional error, (PK2) biexponential with proportional error, (PK2 epsilon) biexponential with additive error, (PD1) Emax model with additive error under the logit transform, and (PD2) sigmoid Emax model with additive error under the logit transform. Six simulation/analysis settings are studied. The first three, (PK1/PK1), (PK2/PK2), and (PD1/PD1) evaluate whether the PPC has appropriate type-I error level, whereas the second three (PK2/PK1), (PK2 epsilon/PK2), and (PD2/PD1) evaluate whether the PPC has adequate power. For a set of 100 data sets simulated/analyzed under each model pair according to a stipulated extensive sampling design, the pPPC is computed for a number of statistics in three different ways (each way uses a different approximation to the posterior distribution on the model parameters). We find that in general; (i) The PPC is conservative under the null in the sense that for many statistics, prob(pPPC < or = alpha) < alpha for small alpha. With respect to such statistics, this means that useful models will rarely be regarded incorrectly as invalid. A high correlation of a statistic with the parameter estimates obtained from the same data used to compute the statistic (a measure of statistical "sufficiency") tends to identify the most conservative statistics. (ii) Power is not very great, at least for the alternative models we tested, and it is especially poor with "statistics" that are in part a function of parameters as well as data. Although there is a tendency for nonsufficient statistics (as we have measured this) to have greater power, this is by no means an infallible diagnostic. (iii) No clear advantage for one or another method of approximating the posterior distribution on model parameters is found.

Ways to fit a PK model with some data below the quantification limit.

Pharmacokinetic data consist of drug concentration measurements, as well as reports of some measured concentrations being below the quantification limit of the assay (BQL). A pharmacokinetic model may befit to these data, and for this purpose, the BQL observations must be either discarded or handled in a special way. In this paper, seven methods for dealing with BQL observations are evaluated. Both single-subject and population data are simulated from a one-compartment model. A moderate amount of data is simulated for each individual. The actual cv of concentration measurements at the quantification limit is assumed to be no greater than 20%, in accord with the FDA Guidance. The results of this paper should be interpreted in this context. The methods include handling BQL observations as fixed-point censored observations, i.e., by using the likelihoods that these observations are in fact BQL. This method is shown to have some overall statistical advantage. However, the gain in using this method over that of simply discarding the BQL observations is not always much, and this is especially so when the frequency of BQL observations is small. Some simple methods entailing (i) replacing one or more BQL observations with the value 0, or (ii) replacing them with the value QL/2, where QL is the quantification limit, are also included. The first of these two approaches should not be used With population data, use of the second approach can result in some noticeably improved estimation of the typical value of a parameter, but then there is also marked degradation in the estimation of the population variance of the parameter.

Specific dangers associated with infants sleeping on sofas.

AIM: A study was undertaken to examine specific circumstances that may lead to accidental asphyxial deaths in infants on sofas. METHODS: Coronial files in South Australia (Australia) from 1989 to 1998, and files at the Office of the Medical Examiner in San Diego County (USA) from 1991 to 1998 were searched for all cases of infant deaths occurring on sofas. RESULTS: A total of 10 cases with complete death scene descriptions were found. Four deaths were attributed to sudden infant death syndrome and six deaths to accidental asphyxia, of which four involved shared sleeping with an adult. Lethal circumstances involved infants being overlayed by an adult (n = 2), wedged between an adult and the back of a sofa (n = 1), sleeping with an intoxicated/sedated adult (n = 2), wedged between pillows and the back of a sofa (n = 1), and wedged into the back of a sofa (n = 1). CONCLUSIONS: Although shared sleeping of an adult with an infant on a sofa may result in accidental asphyxia, there is also the potential for wedging and accidental asphyxia of infants sleeping alone on a sofa. For this reason the use of sofas for both shared and solitary infant sleeping is discouraged.

Sudden infant death syndrome in South Australia 1968-97. Part I: changes over time.

OBJECTIVE: To compare the epidemiology of sudden infant death syndrome (SIDS) over three consecutive decades. METHODOLOGY: The birth history, infant's developmental and health history, infant care practices for the infant, death scene investigation and autopsy findings for all infants dying suddenly and unexpectedly in South Australia (SA) between January 1968 and December 1997 were studied. RESULTS: The incidence of SIDS in SA rose through the 1970s and early 1980s with the highest incidence being in infants born in 1986 at 2.4 per 1000 live births (LB). Two factors felt to be dangerous for some infants were identified being left unobserved in the prone position and having the head covered by bed clothes. Publicity about the risk of prone sleeping has been accompanied by a fall in SIDS deaths, to an incidence of 0.5 per 1000 LB in 1997. The incidence in Aboriginal infants, and infants living in lower socio-economic conditions has always been high, but the over-representation of these groups has increased in the last 5 years. CONCLUSION: It no infant under 8 months of age was placed prone or was able to get to prone unobserved before the age when they can easily get back to supine, and no infant was able to get the head completely covered while unobserved, the incidence of SIDS in SA should fall below 0.2 per 1000 LB.

Sudden infant death syndrome (SIDS) in South Australia 1968-97. Part 2: the epidemiology of non-prone and non-covered SIDS infants.

OBJECTIVE: To identify the risk factors for infants who die suddenly and unexpectedly, but whose deaths are not related to prone position, or having the head covered. METHODOLOGY: A case-control study was designed in which the cases were infants who had died of sudden infant death syndrome (SIDS) in South Australia between January 1974 and December 1997, who were found not prone, not bed sharing and with the head not covered. The controls were two infants for each case, born in the same year and found in the prone position (again not bed sharing and with the head not covered). RESULTS: Sudden unexpected death infancy is rare in non-prone infants with the head not covered. occurring on average twice a year in South Australia, where there are 18,000-21,000 births per year. In this group there was a higher percentage of infants with features associated with low socio-economic groups (teenage pregnancies and maternal smoking), sibling SIDS, suspicion of non-accidental injury and the presence of minor congenital anomalies, especially cardiac anomalies. CONCLUSIONS: The majority of unexpected deaths in infancy can be prevented by not allowing infants to be unobserved in prone position, and by preventing them from getting their faces covered. For the few infants not found in these positions, a careful investigation should be made for malformations or non-accidental injury.

Sudden infant death syndrome in South Australia 1968-97. Part 3: is bed sharing safe for infants?

OBJECTIVE: To examine the risk of death for bed-sharing infants. METHODOLOGY: All unexpected infant deaths occurring in South Australia between 1970 and 1997, occurring after the infant was put to rest and diagnosed by after death scene investigation and autopsy as sudden death infant syndrome, accidental death, or 'undetermined' were studied. RESULTS: Accidents were the most likely cause of death for 5% of infants who died in designated infant containers (cots, cradles, etc), 24% of those who were sharing a bed or couch, and 72% of those who were placed alone on a bed or couch. CONCLUSIONS: While bed sharing showed an increased risk of dying accidentally, when compared with infants sleeping in designated infant containers, the risk of accidental death in this study was even greater for infants left alone on adult beds or couches.

Athetoid quadriplegia and literacy.

OBJECTIVE: To compare literacy levels in athetoid quadriplegic (AQ) patients born in the 1960s and 1970s with those born in the 1980s and 1990s. METHODOLOGY: Nine patients with AQ born between 1966 and 1972 were compared with eight patients born between 1983 and 1991. RESULTS: Reading difficulties were found in almost all patients with AQ, despite normal intellect. Those in the earlier period were for the most part functionally literate, while those in the later period were functionally illiterate. CONCLUSIONS: Specific and intensive reading education may be required in patients with AQ to obtain functional literacy.

Gastric aspiration and sleeping position in infancy and early childhood.

Concern has been expressed that the recommendation of supine sleeping position for infants would result in an increase in deaths due to gastric aspiration. A review of 196 cases of infant and early childhood death in children under 3 years of age, occurring over a 9-year period (September 1989 to August 1998) was undertaken to ascertain how many cases of significant gastric aspiration had occurred. Extensive and widespread filling of the airways/alveoli with gastric contents was found in three infants/young children aged 5, 6 and 30 months, respectively. In each instance the body had been found lying face down (prone), with the face in a pool of vomitus in at least one case. No cases of significant gastric aspiration were found in infants who had been found lying on their sides or backs (supine). In addition, no significant increase in numbers of infant and early childhood deaths in South Australia due to gastric aspiration over this time could be demonstrated. Concerns that the supine rather than the prone position is more likely to result in significant gastric aspiration are not supported by this study.

A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron.

This paper presents and illustrates methodology for specifying, estimating, and evaluating a predictive model for repeated measures time-to-event responses. The illustrative example specifies a model of the antiemetic effect vs. concentration relationship for the 5-HT3 antagonist ondansetron in the human ipecac model for emesis. A key part of this model is a time-dependent log hazard function for emesis that is increased by ipecac administration and decreased by ondansetron concentration. The model is fit using an approximate maximum likelihood method. The data consist of the time free of emeses and, for those individuals with emetic episodes, the time(s) of the episode(s). Model evaluation is accomplished using residual plots adapted to time-to-event data and a "posterior predictive check" wherein observed data statistics are compared to those obtained from data simulated from the fitted model. The ondansetron concentration required to obtain a 50% reduction in the hazard of emesis is estimated to be 1.4 +/- 0.2 ng/ml, and the rate constant for elimination of ipecac-induced hazard is 1.5 +/- 0.2 hr-1.

Non-steady state population kinetics of intravenous phenytoin.

This observational study explored the effects of demographics, sickness, and polypharmacy on the non-steady state population pharmacokinetics of intravenous phenytoin. One hundred fifteen patients were studied. Models were developed using the NONMEM program with hybrid first-order conditional estimation. A Michaelis-Menten model with delayed induction was preferred over a Michaelis-Menten model without induction, a Michaelis-Menten model with immediate induction, or a linear model with delayed induction. When the data were fit to a Michaelis-Menten model with delayed induction, the volume of distribution (Vd) was found to depend on weight and serum albumin. The Vd was estimated to be 0.95 l/kg, assuming an albumin level of 3 g/dl. The Michaelis-Menten constant (km) was estimated to be 7.9 mg/l. The baseline maximum metabolic rate was 580 mg/day for a 70-kg patient. The average time to onset of induction was 59.5 hours. If a fever developed after induction began, it increased the extent of induction. This model was evaluated retrospectively in 26 additional patients, yielding a mean prediction error of -0.4 mg/l (-3.0-2.2 mg/l) and a mean absolute prediction error of 4.7 mg/l (3.2-6.2 mg/l) based on two-level feedback. Given the large interindividual variances in maximum metabolic rate, phenytoin levels should be measured frequently.

Formal retrospective case review and sudden infant death.

A review of 24 consecutive sudden infant deaths was undertaken to evaluate the importance of the various stages in the postmortem assessment of such cases. Death in three cases was caused by obvious trauma. Of the remainder, 16 were attributed to sudden infant death syndrome (SIDS), 4 to accidental asphyxia (identified by death scene examination and/or formal case review) and 1 to a lingual thyroglossal duct cyst. Three (14%) of 21 deaths thought to be SIDS after postmortem examination were attributed to asphyxia following subsequent formal case review.