Outpatient Management of Neonatal Abstinence Syndrome: A Quality Improvement Project.

BACKGROUND: An increasing number of infants are diagnosed with neonatal abstinence syndrome (NAS). The study's primary objectives were to describe an academic medical center's level IV neonatal ICU's (NICU's) comprehensive outpatient NAS management effort, measure guideline compliance, and assess its safety. Secondary objectives were to describe the duration and cumulative methadone exposure, and to improve parent and provider knowledge of NAS. METHODS: The study included 22 infants having a gestational age of 35-41 weeks, diagnosed with NAS, and discharged for outpatient methadone management. Discharges spanned 10 months and included 3 improvement periods. The outpatient program includes comprehensive discharge planning, a focused electronic health record (EHR) template, management guidelines, and parent and provider education. RESULTS: Providers complied with using the outpatient management guideline and EHR template, and assessed weight, NAS symptoms, and methadone dose during appointments. Two infants required NAS-related hospital readmission in the study period. From improvement period 1 to period 3 there was no difference in total outpatient days on methadone (58, 53, 74 days, respectively) or cumulative methadone dose (2.7, 2.6, 3.1mg/kg, respectively). A downward trend pattern in cumulative methadone exposure was noted in improvement period 2. Pre- and postimplementation surveys revealed that after implementation, parents had better understanding of NAS before delivery (71% vs. 100%, p = 0.009), while providers had increased comfort with outpatient management (24% vs. 67%, p < 0.001) and educating parents (48% vs. 82%, p = 0.001). CONCLUSION: This preliminary study suggests that outpatient NAS management can be safe when a comprehensive management program is implemented and can result in provider compliance with the program.

Probiotics for infantile colic: a randomized, double-blind, placebo-controlled trial investigating Lactobacillus reuteri DSM 17938.

OBJECTIVE: To investigate the effectiveness of Lactobacillus reuteri DSM 17938 for the treatment of infantile colic in breastfed Canadian infants, compared with placebo. STUDY DESIGN: A randomized, double-blind, placebo-controlled trial was conducted involving 52 infants with colic, according to modified Wessel criteria, who were assigned at random to receive L reuteri DSM 17938 (10(8) colony-forming units) (n = 24) or placebo (n = 28) for 21 days. Daily crying and fussing times were recorded in a structured diary, and maternal questionnaires were completed to monitor changes in infant colic symptoms and adverse events. RESULTS: Total average crying and fussing times throughout the study (from baseline to day 21) were significantly shorter among infants with colic in the probiotic group compared with infants in the placebo group (1719 ± 750 minutes [29 ± 13 hours] vs 2195 ± 764 minutes [37 ± 13 hours]; P = .028) (relative risk, 0.78; 95% CI, 0.58-0.98). Infants given L reuteri DSM 17938 showed a significant reduction in daily crying and fussing times at the end of treatment period compared with those receiving placebo (median, 60 minutes/day [IQR, 64 minutes/day] vs 102 minutes/day [IQR, 87 minutes/day]; P = .045). On day 21, a significantly higher proportion of infants in the L reuteri DSM 17938 group responded to treatment with a ≥50% crying time reduction compared with infants given placebo (17 vs 6, P = .035; relative risk, 3.3; 95% CI, 1.55-7.03). CONCLUSION: Administration of L reuteri DSM 17938 significantly improved colic symptoms by reducing crying and fussing times in breastfed Canadian infants with colic.

Reduced fertility in vitro in mice lacking the cystatin CRES (cystatin-related epididymal spermatogenic): rescue by exposure of spermatozoa to dibutyryl cAMP and isobutylmethylxanthine.

The cystatin CRES (cystatin-related epididymal spermatogenic; Cst8) is the defining member of a reproductive subgroup of family 2 cystatins of cysteine protease inhibitors and is present in the epididymis and spermatozoa, suggesting roles in sperm maturation and fertilization. To elucidate the role of CRES in reproduction, mice lacking the Cst8 gene were generated and their fertility examined. Although both male and female Cst8(-/-) mice generated offspring in vivo, spermatozoa from Cst8(-/-) mice exhibited a profound fertility defect in vitro. Compared to spermatozoa from Cst8(+/+) mice, spermatozoa from Cst8(-/-) mice were unable to undergo a progesterone-stimulated acrosome reaction and had decreased levels of protein tyrosine phosphorylation, suggesting a defect in the ability of Cst8(-/-) spermatozoa to capacitate. Incubation of Cst8(-/-) spermatozoa with dibutyryl cAMP and 3-isobutyl-1-methylxanthine rescued the fertility defect, including the capacity for sperm protein tyrosine phosphorylation. Both untreated Cst8(+/+) and Cst8(-/-) spermatozoa, however, exhibited similar increased total levels of cAMP and protein kinase A (PKA) activity throughout the capacitation time course compared to spermatozoa incubated under noncapacitating conditions. Taken together, these results suggest that mice lacking CRES may have altered local levels of cAMP/PKA activity, perhaps because of improper partitioning or tethering of these signaling molecules, or that the CRES defect does not directly involve cAMP/PKA but other signaling pathways that regulate protein tyrosine phosphorylation and capacitation.

Early and frequent exposure to antibiotics in children and the risk of obesity: systematic review and meta-analysis of observational studies.

Background: This study aimed to systematically evaluate the available evidence on prenatal and early infancy antibiotic exposure and the association with overweight and obesity in later childhood. Methods: We conducted a comprehensive search of Embase, MEDLINE, and Web of Science for observational studies assessing prenatal and early antibiotic exposure on the risk of overweight and obesity. We independently assessed the risk of bias using the ROBINS instrument and the overall quality of evidence using the GRADE approach. Results: Our search identified thirteen observational studies including 554,983 participants; most studies were at moderate risk of bias. We found a statistically significant impact of early antibiotic exposure and the risk of being overweight later in childhood (OR 1.18; 95% CI 1.05 to 1.34) (very low quality evidence). We also found that early childhood antibiotic exposure was associated with the risk for childhood obesity (OR 1.14; 95% CI 1.04 to 1.24) (very low quality evidence). Conclusions: Very low quality evidence suggests that exposure to antibiotics early in life may be associated with an increased risk of being overweight and obese in later childhood.  However, very low quality evidence raises serious questions about the plausibility of prenatal and early infancy antibiotic exposure being causally related to weight in children. PROSPERO registration: CRD42016050011 (14/12/2016).

Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA.

Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92-0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis.

CONTEXT: Lactobacillus reuteri DSM17938 has shown promise in managing colic, but conflicting study results have prevented a consensus on whether it is truly effective. OBJECTIVE: Through an individual participant data meta-analysis, we sought to definitively determine if L reuteri DSM17938 effectively reduces crying and/or fussing time in infants with colic and whether effects vary by feeding type. DATA SOURCES: We searched online databases (PubMed, Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Database of Abstracts of Reviews of Effects, and Cochrane), e-abstracts, and clinical trial registries. STUDY SELECTION: These were double-blind randomized controlled trials (published by June 2017) of L reuteri DSM17398 versus a placebo, delivered orally to infants with colic, with outcomes of infant crying and/or fussing duration and treatment success at 21 days. DATA EXTRACTION: We collected individual participant raw data from included studies modeled simultaneously in multilevel generalized linear mixed-effects regression models. RESULTS: Four double-blind trials involving 345 infants with colic (174 probiotic and 171 placebo) were included. The probiotic group averaged less crying and/or fussing time than the placebo group at all time points (day 21 adjusted mean difference in change from baseline [minutes] -25.4 [95% confidence interval (CI): -47.3 to -3.5]). The probiotic group was almost twice as likely as the placebo group to experience treatment success at all time points (day 21 adjusted incidence ratio 1.7 [95% CI: 1.4 to 2.2]). Intervention effects were dramatic in breastfed infants (number needed to treat for day 21 success 2.6 [95% CI: 2.0 to 3.6]) but were insignificant in formula-fed infants. LIMITATIONS: There were insufficient data to make conclusions for formula-fed infants with colic. CONCLUSIONS: L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research.

Extracellular quality control in the epididymis.

The epididymal lumen represents a unique extracellular environment because of the active sperm maturation process that takes place within its confines. Although much focus has been placed on the interaction of epididymal secretory proteins with spermatozoa in the lumen, very little is known regarding how the complex epididymal milieu as a whole is maintained, including mechanisms to prevent or control proteins that may not stay in their native folded state following secretion. Because some misfolded proteins can form cytotoxic aggregate structures known as amyloid, it is likely that control/surveillance mechanisms exist within the epididymis to protect against this process and allow sperm maturation to occur. To study protein aggregation and to identify extracellular quality control mechanisms in the epididymis, we used the cystatin family of cysteine protease inhibitors, including cystatin-related epididymal spermatogenic and cystatin C as molecular models because both proteins have inherent properties to aggregate and form amyloid. In this chapter, we present a brief summary of protein aggregation by the amyloid pathway based on what is known from other organ systems and describe quality control mechanisms that exist intracellularly to control protein misfolding and aggregation. We then present a summary of our studies of cystatin-related epididymal spermatogenic (CRES) oligomerization within the epididymal lumen, including studies suggesting that transglutaminase cross-linking may be one mechanism of extracellular quality control within the epididymis.

Application of surrogate methods for assessing the bioavailability of PAHs in sediments to a sediment ingesting bivalve.

The usefulness of two surrogate methods for rapidly determining the bioavailability of PAHs in hydrocarbon-contaminated marine sediments was assessed. Comparisons are made between the PAHs accumulated by the benthic bivalve, Tellina deltoidalis, and the extractable-PAHs determined using a 6-h XAD-2 resin desorption method and a 4-h gut fluid mimic (GFM) extraction method. There were significant positive relationships between PAH bioaccumulation by the bivalves and sediment PAH concentrations. These relationships were not improved by normalising the sediment PAH concentrations to the organic carbon concentration. The average percentage lipid content of the bivalves was 1.47+/-0.22% and BSAFs for total-PAHs ranged from 0.06 to 0.80 (kgOC/kg lipid). The XAD-2 and GFM methods both extracted varying amounts of PAHs from the sediments. Low concentrations of PAHs were extracted by the GFM method (0.2-3.6% of total-PAHs in sediments) and the GFM results were inadequate for generalising about the bioavailability of the PAHs in the sediments. The XAD-2 method extracted greater amounts of PAHs (3-34% of total-PAHs in sediments), however, the total-PAH concentrations in the sediments provided a better, or equally good, prediction of PAH bioaccumulation by T. deltoidalis. The results indicated that these methods required further development before they can be applied routinely as surrogate methods for assessing the bioavailability of PAHs in sediments. Future research should be directed towards lowering detection limits and obtaining comparative data for a greater range of sediment types, contaminant classes and concentrations, and organisms of different feeding guilds and with different gut chemistry.

The principle of equipoise in pediatric drug trials.

Equipoise is a fundamental ethical principle in the conduct of interventional trials comparing two or more treatment arms. This principle dictates that, at the time of planning and executing such trials, the researchers must have no compelling evidence that one arm is superior to the other arm(s). That means that it is unethical to involve patients in a study where one intervention is convincingly better than the other, as this would mean that a group of patients will receive an inferior option, which may endanger their health. While this principle may be straightforward at the beginning of a trial, there are numerous ways how it may be subsequently disrupted. Presently, most of the literature on equipoise deals with adult patients, with very little experience in children. This paper illustrates the principle of equipoise and the process of defining it. Because the majority of pediatric medications have not been studied adequately and are not labeled for pediatric use, it is often challenging to decide whether equipoise exists for a certain pharmacological treatment. Moreover, the equipoise may dynamically change during the conduct of a study, if new evidence from other studies becomes available.

Are selective serotonin reuptake inhibitors a secondary cause of low bone density?

Background. Osteoporosis is a chronic disease that can significantly impact numerous aspects of health and wellness. The individual consequences of osteoporosis can be devastating, often resulting in substantial loss of independence and sometimes death. One of the few illnesses with greater disease burden than low bone mineral density (BMD) is major depressive disorder (MDD). Both depression and antidepressant use have been identified as secondary causes of osteoporosis. The objective of this paper is to review and summarize the current findings on the relationship between antidepressant use and BMD. Methods. Relevant sources were identified from the Pubmed and MEDLINE databases, citing articles from the first relevant publication to September 1st, 2010. Results. 2001 articles initially met the search criteria, and 35 studies were thoroughly reviewed for evidence of an association between SSRI use and BMD, and 8 clinical studies were detailed and summarized in this paper. Conclusions. Current findings suggest a link between mental illness and osteoporosis that is of clinical relevance. Additional longitudinal studies and further research on possible mechanisms surrounding the association between SSRI use on bone metabolism need to be conducted. Treatment algorithms need to recognize this association to ensure that vulnerable populations are screened.