Benjamin Mayer

Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants

BACKGROUND & AIMS Probiotics have been suggested to prevent severe necrotizing enterocolitis (NEC) and decrease mortality in preterm infants. The aim of this paper was to systematically analyze the level of evidence (LoE) of published controlled randomized trials (RCTs) on probiotics in preterm infants. METHODS Literature searches were made up to November 2010. LoE of recommendations based on single trials or meta-analyses were scored following the Oxford Center for Evidence based Medicine approach (1a - meta-analyses of 1b LoE studies; 1b - well designed RCT; 2a - meta-analyses which include 2b LoE studies; 2b - lesser quality RCT). RESULTS Fifteen trials were included (Two 1b LoE trials and thirteen 2b LoE trials). Methodological assessment revealed considerable heterogeneity. Some probiotics may be beneficial in relation to reduction of severe NEC (2b LoE) and reduction of mortality (2b LoE). Probiotics do not accelerate feeding advancement (1b and 2b LoE). There was no convincing benefit with regard to prevention of sepsis (1b and 2b LoE). CONCLUSION There is insufficient evidence to recommend routine probiotics. However, there is encouraging data (2b LoE) which justifies the further investigation regarding the efficacy and safety of specific probiotics in circumstances of high local incidence of severe NEC.

Systematic review and meta-analysis of antibiotic prophylaxis in severe acute pancreatitis

Abstract Objective. The incidence of acute pancreatitis varies from 5 to 80 per 100,000 throughout the world. The most common cause of death in these patients is infection of pancreatic necrosis by enteric bacteria, spurring the discussion of whether or not prophylactic antibiotic administration could be a beneficial approach. In order to provide evidence of the effect of antibiotic prophylaxis in severe acute pancreatitis (SAP) we performed an updated systematic review and meta-analysis on this topic. Methods. The review of randomized controlled trials was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. We conducted a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. For assessment of the treatment effects we calculated the risk ratios (RRs) for dichotomous data of included studies. Results. Fourteen trials were included with a total of 841 patients. The use of antibiotic prophylaxis was not associated with a statistically significant reduction in mortality (RR 0.74 [95% CI 0.50–1.07]), in the incidence of infected pancreatic necrosis (RR 0.78 [95% CI 0.60–1.02]), in the incidence of non-pancreatic infections (RR 0.70 [95% CI 0.46–1.06]), and in surgical interventions (RR 0.93 [95% CI 0.72–1.20]). Conclusion. In summary, to date there is no evidence that supports the routine use of antibiotic prophylaxis in patients with SAP.

Polymerase chain reaction and Southern blot-based analysis of the C9orf72 hexanucleotide repeat in different motor neuron diseases

The GGGGCC-hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. This study determined the frequency of C9orf72 repeat expansions in different motor neuron diseases (amyotrophic lateral sclerosis (ALS), motor neuron diseases affecting primarily the first or the second motor neuron and hereditary spastic paraplegia). Whereas most studies on C9orf72 repeat expansions published so far rely on a polymerase chain reaction-based screening, we applied both polymerase chain reaction-based techniques and Southern blotting. Furthermore, we determined the sensitivity and specificity of Southern blotting of the C9orf72 hexanucleotide repeat in DNA derived from lymphoblastoid cell lines. C9orf72 repeat expansions were found in 27.1% out of 166 familial ALS patients, only once in 68 sporadic ALS patients, and not in 61 hereditary spastic paraplegia patients or 52 patients with motor neuron diseases affecting clinically primarily either the first or the second motor neuron. We found hints for a correlation between C9orf72 repeat length and the age of onset. Somatic instability of the C9orf72 repeat was observed in lymphoblastoid cell lines compared with DNA derived from whole blood from the same patient and therefore caution is warranted for repeat length determination in immortalized cell lines.

A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany

Mutations in the optineurin (OPTN) gene have been associated with normal tension glaucoma and with amyotrophic lateral sclerosis (ALS). Here, we screened German familial ALS cases for OPTN mutations to gain additional insight into the spectrum and pathogenic relevance of this gene for ALS. One hundred familial German ALS cases and 148 control subjects were screened for OPTN mutations by sequence analysis of the complete OPTN coding sequence, and phenotypes of OPTN mutant patients were described. We identified a novel heterozygous truncating OPTN mutation p.Lys440Asnfs*8 in 1 ALS family with an aggressive ALS disease phenotype. This mutation abolishes protein domains crucial for nuclear factor κB signaling. Moreover, we detected 3 different nonsynonymous sequence variants, which have been described previously as risk factors for primary retinal ganglion cell degeneration in normal tension glaucoma. Two of them were detected on the same allele in a family that also carries a p.Asn352Ser disease mutation in the ALS gene TARDBP. All OPTN mutant patients presented with typical spinal onset ALS. Taken together, we detected a novel truncating OPTN mutation associated with an aggressive form of ALS and confirmed that OPTN mutations are a rare cause of ALS. In addition our data suggest that in some cases plausibly more than 1 mutation in OPTN or another ALS gene might be needed to cause ALS. Finally, our findings show that motoneurons and retinal ganglion cells, which are both projecting central nervous system neurons, might share common susceptibility factors.

Pain characteristics and pain control in European nursing homes: cross-sectional and longitudinal results from the Services and Health for Elderly in Long TERm care (SHELTER) study.

OBJECTIVE AND DESIGN Few studies have compared cross-national characteristics of residents with pain in European long term care facilities. The SHELTER project, a cross-national European study on nursing home residents, provides the opportunity to examine this issue. The present study aimed to evaluate key figures about pain and compare them with seven European countries and Israel. SETTING, PARTICIPANTS, AND MEASUREMENTS A total of 3926 nursing home residents were assessed by the interRAI instrument for Long Term Care Facilities (interRAI LTCF). Prevalence of pain, frequency, intensity, consistency, and control were estimated and compared cross-nationally. Correlates between patient-related characteristics and inadequate pain management were tested using bivariate and multivariate logistic regression models. RESULTS Overall, 1900 (48.4%) residents suffered from pain. Pain prevalence varied significantly among countries, ranging from 19.8% in Israel to 73.0% in Finland. Pain was positively associated with female gender, fractures, falls, pressure ulcers, sleeping disorders, unstable health conditions, cancer, depression, and number of drugs. It was negatively associated with dementia. In a multivariate logistic regression model, all associations remained except for sleeping disorders. Clinical correlations varied considerably among countries. Although in 88.1% of cases, pain was self-rated by the residents as sufficiently controlled, in only 56.8% of cases was pain intensity self-rated as absent or mild. Pain control and intensity improved within 1 year. CONCLUSION Pain prevalence is high and varies considerably across Europe. Although most residents considered pain as adequately controlled, a closer look confirmed that many still suffer from high pain intensities. Analyzing the reasons behind these differences may help to improve pain management.

Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers

Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

Semen enhances HIV infectivity and impairs the antiviral efficacy of microbicides

Endogenous amyloids in semen impair the antiretroviral efficacy of drugs targeting HIV directly, but do not impair maraviroc, which targets the cellular CCR5 receptor. Undermining Antiretroviral Drug Activity HIV microbicides potently inhibit the virus in vitro but have failed in clinical trials. Semen is a vector for mediating HIV transmission, and the amyloid fibrils in semen have been shown to boost HIV infectivity. Zirafi et al. now show that semen impairs the antiviral efficacy of microbicides that target HIV components. Only the microbicide maraviroc, which binds to the host CCR5 co-receptor for HIV entry, retains full antiviral activity in the presence of semen. These results help to explain why current microbicides have fallen short in performance when tested in clinical trials. These findings further suggest that future in vitro testing of microbicides should be performed in the presence of semen to better predict the antiretroviral efficacy in vivo. Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. We report that candidate microbicides that target HIV components show greatly reduced antiviral efficacy in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity was dependent on the ability of amyloid fibrils in semen to enhance the infectivity of HIV. Thus, the anti-HIV efficacy of microbicides determined in the absence of semen greatly underestimated the drug concentrations needed to block semen-exposed virus. One notable exception was maraviroc. This HIV entry inhibitor targets the host cell CCR5 co-receptor and was highly active against both untreated and semen-exposed HIV. These data help to explain why microbicides have failed to protect against HIV in clinical trials and suggest that antiviral compounds targeting host factors hold promise for further development. These findings also suggest that the in vitro efficacy of candidate microbicides should be determined in the presence of semen to identify the best candidates for the prevention of HIV sexual transmission.

Stigma as a stressor and transition to schizophrenia after one year among young people at risk of psychosis

According to stress-vulnerability models, social stressors contribute to the onset of schizophrenia. Stigma and discrimination associated with mental illness may be a stressor for young people at risk of psychosis even prior to illness onset, but quantitative longitudinal data on this issue are lacking. We examined the cognitive appraisal of stigma-related stress as predictor of transition to schizophrenia among young people at risk of psychosis. In Zürich, Switzerland, 172 participants between 13 and 35years old and with either high or ultra-high risk of psychosis or risk of bipolar disorder were included. With 71 dropouts, transition was assessed during 12months among 101 participants of whom 13 converted to schizophrenia. At baseline, the cognitive appraisal of stigma as a stressor was measured by self-report, based on the primary appraisal of stigma as harmful and the secondary appraisal of resources to cope with stigma. Positive and negative symptoms were examined using the Positive and Negative Syndrome Scale. Compared with participants who did not convert to schizophrenia, converters had significantly more positive (p<.001) and negative (p<.001) symptoms and reported higher levels of stigma-related harm (p=.003) and stress (p=.009) at baseline. More perceived harm due to stigma at baseline predicted transition to schizophrenia (odds ratio 2.34, 95%-CI 1.19-4.60) after adjusting for age, gender, symptoms and functioning. Stigma stress may increase the risk of transition to schizophrenia. Research is needed on interventions that reduce public negative attitudes towards young people at risk and that support individuals at risk to cope with stigma-related stress.

The effect of age on the shape of the BMI–mortality relation and BMI associated with minimum all-cause mortality in a large Austrian cohort

Background:It is unclear if the body mass index (BMI) associated with minimum all-cause mortality is constant throughout adult life or increasing with age.Methods:We applied multivariable fractional polynomials to the data of the Vorarlberg Health Monitoring and Prevention Program to quantify the BMI associated with minimum mortality over age. The analysis included data of 129 904 never-smoking women and men (mean age: 45.4 years) who were followed for a median of 18.6 years.Results:Optimum BMI in women increased with age, lying within the normal BMI category (according to the World Health Organization definition) from the age of 20 years (23.3 kg m−2, 95% confidence interval (CI): 22.2–24.3) to the age of 54 years and in the lower half of the overweight category from the age of 55 years onwards, reaching 26.2 kg m−2 (95% CI: 25.1–27.3) at the age of 69 years. In men, optimum BMI increased slightly from 23.7 kg m−2 (95% CI: 22.1–25.2) at the age of 20 years until the age of 59 years, reaching a BMI of 25.4 kg m−2 (95% CI: 24.8–26.0) and decreased afterwards to 22.7 kg m−2 (95% CI: 20.9–24.6) at the age of 80 years.Conclusions:Our results indicate that BMI associated with minimum all-cause mortality changes with age and that patterns differ by sex. Sex- and age-independent BMI recommendations might therefore be inappropriate. Further studies using flexible methods instead of predefined categories are necessary to revise BMI recommendations.

Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis

Objective To examine neurofilament (Nf) concentrations according to symptom onset and clinical diagnostic certainty categories of amyotrophic lateral sclerosis (ALS). Methods We measured Nf light chain (NfL) and phosphorylated Nf heavy chain (pNfH) CSF and NfL serum levels in patients with ALS with first symptom onset ≤6 months (n = 54) or >6 months (n = 135) from sampling, and patients with other neurologic diseases, differential diagnoses of a motor neuron disease (MND mimics), and other MND variants to determine the diagnostic accuracy in patients with ALS with early symptom onset. Samples were received multicentric and analyzed by ELISA and Simoa platform and related to other clinical measures. Results NfL and pNfH in CSF and NfL in serum were increased in early and later symptomatic phase ALS (p < 0.0001). CSF and serum NfL and CSF pNfH discriminated patients with ALS with early symptom onset from those with other neurologic diseases and MND mimics with high sensitivity (94%, 88%, 98%, and 89%, 100%, 78%) and specificity (86%, 92%, 91%, and 94%, 90%, 98%) and did not vary between clinical diagnostic categories of ALS in the early symptomatic phase group. Baseline NfL and pNfH levels were not significantly different in patients with ALS with clinical progression to definite or probable ALS at follow-up. Conclusion The measurement of Nf has potential to enhance diagnostic accuracy of ALS in those presenting soon after symptom onset, and is measurable across multiple centers. Classification of evidence This study provides Class II evidence that CSF and serum Nf concentrations discriminate ALS with early symptom onset from other neurologic diseases.