Increased type-I interferon level is associated with liver damage and fibrosis in primary sclerosing cholangitis.

BACKGROUND: The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression. METHODS: Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients' sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study. RESULTS: Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2-deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, ß and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC. CONCLUSIONS: The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.

[Malpractice Claims Against Pediatricians - Analysis of Expert Testimonies from the Medical Service of Health Insurance Companies Between 2000 and 2014]. / Behandlungsfehlervorwürfe gegen Pädiater ­ eine Analyse von Gutachten des Medizinischen Dienstes der Krankenversicherung der Jahre 2000 bis 2014.

Background In Germany, few data are available on medical malpractice claims against pediatricians. On behalf of Statutory Health Insurance Companies their Medical Service (MDK) regularly offers expert testimony in case of allegations during pediatric treatment. Methods Analysis of 374 written pediatric testimonies, documented between September 1st, 2000 and August 31st, 2014. Results 193 allegations against pediatricians were analysed separately for each sector of care (35% concerning outpatients, 28% normal inpatients, and 37% patients treated in an intensive care unit, ICU). Outpatient care led more frequently to malpractice claims regarding diagnosis, most often in the case of dysplasia of the hip (n=6), meningitis (n=5), and pneumonia (n=4). In inpatients, allegations regarding treatment errors were more common and frequently associated with extravasation injury (n=7), as well as periventricular leukomalacia (n=7), sepsis (=6), and intraventricular haemorrhage (n=4) in newborn infants on ICUs. Expert testimony confirmed allegations in 43% of the outpatients, 22% of the normal inpatients and 38% of the ICU patients. Discussion and conclusion The frequency of pediatric malpractice claims seems to depend primarily on the pattern of utilization of pediatric care services. Diagnosis-related constellations leading to malpractice claims in Germany are well-known internationally. Case analysis according to medical care sectors allows comprehensible conclusions for risk management.

Mortality and Major Morbidity of Very-Low-Birth-Weight Infants in Germany 2008-2012: A Report Based on Administrative Data.

BACKGROUND: Expectant parents of very preterm infants, physicians, and policy makers require estimates for chances of survival and survival without morbidity. Such estimates should derive from a large, reliable, and contemporary data base of easily available items known at birth. OBJECTIVE: To determine short-term outcome and risk factors in very-low-birth-weight preterm infants based on administrative data. METHODS: Anonymized routine data sets transmitted from hospital administrations to statutory health insurance companies were used to assess survival and survival free of major morbidities in a large cohort of preterm infants in Germany. RESULTS: After exclusion of infants with lethal malformations, there were 13,147 infants with a birth weight below 1,500 g admitted to neonatal care 2008-2012, of whom 1,432 infants (10.9%) died within 180 days. Estimated 180 days survival probabilities were 0.632 (95% confidence interval 0.583-0.677) for infants with 250-499 g birth weight, 0.817 (0.799-0.834) for 500-749 g, 0.931 (0.920-0.940) for 750-999 g, 0.973 (0.967-0.979) for 1,000-1,249 g, and 0.985 (0.981-0.988) for 1,250-1,499 g. Estimated probabilities for survival without major morbidity (surgically treated intraventricular hemorrhage, necrotizing enterocolitis, intestinal perforation, or retinopathy) were 0.433 (0.384-0.481) for 250-499 g, 0.622 (0.600-0.643) for 500-749 g, 0.836 (0.821-0.849) for 750-999 g, 0.938 (0.928-0.946) for 1,000-1,249 g, and 0.969 (0.964-0.974) for 1,250-1,499 g, respectively. Prediction of survival and survival without major morbidities was moderately improved by adding sex, small for gestational age, and severe or moderate congenital malformation, increasing receiver operating characteristic areas under the curve from 0.839 (0.827-0.850) to 0.862 (0.852-0.874) (survival) and from 0.827 (0.822-0.842) to 0.852 (0.846-0.863) (survival without major morbidities), respectively. CONCLUSION: The present analysis encourages attempts to use administrative data to investigate the association between risk factors and outcome in preterm infants.

A gap between Need and Reality: Neonatal Nursing Staff Requirements on a German Intensive Care Unit.

Recently, new staffing rules for neonatal nurses in intensive care units (ICU) were issued in Germany, using categories of care of the British Association of Perinatal Medicine as blueprint. Neonates on intensive care require a nurse-to-patient ratio of 1:1, on intensive surveillance (high dependency care) of 1:2. No requirements exist for special care, transitional care, and pediatric ICU patients. Using these rules, nursing staff requirement was calculated over a period of 31 consecutive days once a day in a combined pediatric and neonatal ICU of a metropolitan academic medical center in southwest Germany. Each day, 18.9±0.98 patients (mean±standard deviation) were assessed (14.26±1.21 neonatal, 4.65±0.98 pediatric). Among neonates, 9.94±2.56 received intensive therapy, 3.77±1.85 intensive surveillance, and 0.65±0.71 special care. Average nursing staff requirement was 12.10±1.81 full time equivalents (FTE) per shift. Considering additional pediatric patients in the ICU and actual nursing staff availability (8.97±0.87 FTE per shift), this ICU seems understaffed.

Necrotizing enterocolitis and focal intestinal perforation in neonatal intensive care units in the state of baden-württemberg, Germany.

In preterm infants with very low birth weight (VLBW) <1500 g the most important acquired intestinal diseases are necrotising enterocolitis (NEC) and focal intestinal perforation (FIP). We analyzed data of the neonatology module of national external comparative quality assurance for inpatients in the state of Baden-Württemberg, Germany. Between 2010 and 2012, 59 of 3549 VLBW infants developed FIP (1.7%), 128 of them NEC (3.6%). In approximately 3% of infants with BW<1000 g FIP was diagnosed, which was nearly 9 times more often than in infants with BW between 1250 and 1499 g (FIP frequency 0.36%). NEC frequency increased with decreasing BW and was more than 10 times higher in the smallest infants (BW<750 g: 7.87%) compared to those with BW between 1250 and 1499 g (0.72%). The BW limit of 1250 g differentiates between groups of patients with distinguished risks for NEC and FIP.

Sensitivity analysis of weight reduction results of an observational cohort study in overweight and obese children and adolescents in Germany: the evakuj study.

In the German EvAKuJ observational cohort study, changes in the body mass index standard deviation score (BMI-SDS) of overweight and obese children and adolescents as primary outcome of multimodal (short, inpatient or long, outpatient) weight-loss interventions are difficult to interpret. Published intention-to-treat (ITT) and per protocol data obtained at the end of the intervention (T1), one year (T2), and two years (T3) after its end were used for sensitivity analysis of treatment success rates. The odds ratio and the number needed to treat (NNT) for BMI-SDS reduction of at least -0.2 (successful treatment) and at least -0.5 (good treatment success) were related to spontaneous BMI-SDS reduction rates in a hypothetical control group (control event rate, CER). At T1, treatment seems to be effective up to a CER of 10% in inpatients and of 5% in outpatients. ITT analysis, compromised by a loss to follow-up of 81 to 90% (inpatients) and 57 to 66% (outpatients), indicated that treatment may become less effective at a CER above 1% in inpatients (e.g., successful treatment at T2: NNT=106, at T3: NNT=51), and above 5% in outpatients (successful treatment at T2: NNT=7, at T3: NNT=8; good treatment success at T2 and T3: NNT=25). Positive short-term effects of inpatient treatment of overweight and obese children and adolescents may not be maintained in the long term. Long-term effectiveness of outpatient treatment may depend on age and the degree of overweight.

Delayed detection of cytomegalovirus-specific T-helper cells in a preterm infant following intrauterine exposure to tacrolimus.

After exposure to tacrolimus and CMV reactivation in utero, a preterm infant had a positive CMV polymerase chain reaction (PCR) in urine on day 2 of life. Naive T-cells were reduced, but stimulation with CMV antigen and a polyclonal T-cell activator in vitro yielded no measurable CD4+ T-cell response. When repeated on day 30, polyclonal activation was in the range of healthy adults, while the immune response to CMV was incomplete with a lack of IFNgamma+ CD4+ T-cells and no anti-CMV IgM. Thus, exposure to tacrolimus in utero caused a transitional T-cell activation defect which did not compromise viral clearance.

Immune Reconstitution During the First Year of Antiretroviral Therapy of HIV-1-Infected Adults in Rural Burkina Faso.

There are no data on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected adults in rural Burkina Faso. We therefore assessed CD4(+) T-cell counts and HIV-1 plasma viral load (VL), the proportion of naive T-cells (co-expressing CCR7 and CD45RA) and T-cell activation (expression of CD95 or CD38) in 61 previously untreated adult patients from Nouna, Burkina Faso, at baseline and 2 weeks, 1, 3, 6, 9 and 12 months after starting therapy. Median CD4(+) T-cell counts increased from 174 (10(th)-90(th) percentile: 33-314) cells/µl at baseline to 300 (114- 505) cells/µl after 3 months and 360 (169-562) cells/µl after 12 months of HAART. Median VL decreased from 5.8 (4.6- 6.6) log10 copies/ml at baseline to 1.6 (1.6-2.3) log10 copies/ml after 12 months. Early CD4(+) T-cell recovery was accompanied by a reduction of the expression levels of CD95 and CD38 on T-cells. Out of 42 patients with complete virological follow-up under HAART, 19 (45%) achieved concordant good immunological (gain of ≥100 CD4(+) T-cells/µl above baseline) and virological (undetectable VL) responses after 12 months of treatment (intention-to-treat analysis). Neither a decreased expression of the T-cell activation markers CD38 and CD95, nor an increase in the percentage of naive T-cells reliably predicted good virological treatment responses in patients with good CD4(+) T-cell reconstitution. Repeated measurement of CD4(+) T-cell counts during HAART remains the most important parameter for immunologic monitoring. Substitution of repeated VL testing by determination of T-cell activation levels (e.g., CD38 expression on CD8(+) T-cells) should be applied with caution.

Activation and maturation of peripheral blood T cells in HIV-1-infected and HIV-1-uninfected adults in Burkina Faso: a cross-sectional study.

BACKGROUND: We wanted to explore to what extent environmental exposure to immune stimulants, which is expected to be more present in rural than in urban settings, influences T cell activation and maturation in healthy and in HIV-1-infected individuals in Burkina Faso in west Africa. METHODS: The proportion of circulating naïve T cells and the expression of the T cell activation markers, CD95 and CD38, were analyzed by immunophenotyping and three-colour flow cytometry in 63 healthy individuals and 137 treatment-naïve HIV-1-infected subjects from Ouagadougou (urban setting) and 26 healthy adults and 61 treatment-naïve patients from Nouna (rural). RESULTS: A slightly higher activation level of CD4(+) and CD8(+) peripheral blood T cells was seen in healthy adults living in Nouna than in those living in Ouagadougou. The percentages of naïve CD45RA(bright) CCR7(+) T cells were not significantly different between both study sites. Taking into consideration that relatively more HIV-1-infected patients in Nouna were in an advanced disease stage, no relevant differences were seen in T cell activation and maturation between patients at both study sites. As expected, the percentage of CD95(+) CD4(+) and CD38(+) CD8(+) T cells and the respective antigen density on these cells was significantly higher in patients than in controls in both settings. The percentage of naïve CD8(+) T cells was lower in HIV-1-infected subjects than in healthy controls irrespective of the study site, while a lower proportion of naïve CD4(+) T cells in patients compared with controls was seen only in Nouna. CONCLUSIONS: Environmentally triggered immune activation may contribute to the increased expression of the activation markers CD95 and CD38 on peripheral blood T cells from healthy adults living in rural versus urban settings in Burkina Faso. T cell activation is further increased in HIV-1-infected individuals due to T cell loss and high plasma viral load levels. The observed variations in T cell activation levels or the proportion of naïve T cells in our study patients, however, are not explained by differences in CD4(+) T cell counts or HIV-1 plasma viral load levels alone.

Cross-clade recognition of HIV-1 CAp24 by CD4+ T cells in HIV-1-infected individuals in Burkina Faso and Germany.

The presence of antigen-specific cellular immune responses may be an indicator of long-term asymptomatic HIV-1-disease. The detection of cellular immune responses to infection with different subtypes of HIV-1 may be hampered by genetic differences of immunodominant antigens such as the capsid protein CAp24. In Nouna, Burkina Faso, HIV-1 circulating recombinant forms CRF02_AG and CRF06_cpx are the 2 major strains detectable in HIV-1-infected individuals, while subtype B strains prevail in Europe and North America. Amino acid sequences of CAp24 were assessed in blood samples from 10 HIV-1-infected patients in Nouna, Burkina Faso. Production of interferon-gamma (IFN-gamma) in peripheral blood CD4(+) lymphocytes in response to recombinant HIV-1 proteins derived from clade B (including CAp24(NL4-3)) was measured using a modified flow-cytometry-based whole blood short term activation assay (FASTimmune, BDBiosciences). IFN-gamma production following stimulation with a whole length CAp24 protein derived from clade B (CAp24(NL4-3)) was additionally quantified in comparison to a CAp24 protein derived from CRF02_AG (CAp24(BD6-15)) in 16 HIV-1-infected patients in Heidelberg, Germany. Amino acid sequence identity of CAp24 obtained from patients in Nouna ranged between 86 and 89% when compared to the clade B CAp24(NL4-3) consensus sequence, between 90 and 95% when compared to the circulating recombinant form CRF06_CPX consensus sequence, and between 92 and 96% when compared to the CAp24(BD6-15) consensus sequence. Significant numbers of HIV-1-specific CD4(+) lymphocytes producing IFN-gamma were detected in 4 of 10 HIV-1-infected patients. In 7 of 16 patients in Heidelberg, recombinant CAp24(BD6-15) stimulated IFN-gamma-production in CD4(+) lymphocytes to a similar extent as the clade B-derived CAp24(NL4-3). Thus, antigen-specific CD4(+) lymphocytes from both West African and European patients infected with different strains of HIV-1 show relevant cross-clade recognition of HIV-1 CAp24 in a flow-cytometry-based whole blood short term activation assay.

Breast milk as the "water that supports and preserves life"--socio-cultural constructions of breastfeeding and their implications for the prevention of mother to child transmission of HIV in sub-Saharan Africa.

OBJECTIVES: Complementary breastfeeding represents an important source of risk of HIV infection for infants born to HIV positive mothers. The World Health Organisation recommends that infants born to HIV positive mothers receive either replacement feeding or exclusive breastfeeding (EBF) followed by early weaning. Beyond the clinical and epidemiological debate, it remains unclear how acceptable and feasible the two options are for rural populations in sub-Saharan Africa. This qualitative study aims to fill this gap in knowledge by exploring both the socio-cultural construction and the practice of breastfeeding in the Nouna Health District, rural Burkina Faso. METHODS: Information was collected through 32 individual interviews and 3 focus group discussions with women of all ages, and 6 interviews with local guérisseurs. RESULTS: The findings highlight that breastfeeding is perceived as central to motherhood, but that women practice complementary, rather than exclusive, breastfeeding. The findings also indicate that women recognise both the nutritional value of breast milk and its potential to act as a source of disease transmission. CONCLUSIONS: The findings suggest that given the socio-cultural importance attributed to breastfeeding and the prevailing poverty, it may be more acceptable and more feasible to promote EBF followed by early weaning than replacement feeding. A set of operational strategies are proposed to favour the prevention of mother to child transmission of HIV in the respect of the local socio-cultural setting.

A qualitative investigation into knowledge, beliefs, and practices surrounding mastitis in sub-Saharan Africa: what implications for vertical transmission of HIV?

BACKGROUND: Mastitis constitutes an important risk factor in HIV vertical transmission. Very little, however, is known on how women in sub-Saharan Africa conceptualise health problems related to breastfeeding, such as mastitis, and how they act when sick. We aimed at filling this gap in knowledge, by documenting the indigenous nosography of mastitis, health seeking behaviour, and remedies for prophylaxis and treatment in rural sub-Saharan Africa. METHODS: The study was conducted in the Nouna Health District, rural Burkina Faso. We employed a combination of in-depth individual interviews and focus group discussions reaching both women and guérisseuers. All material was transcribed, translated, and analysed inductively, applying data and analyst triangulation. RESULTS: Respondents perceived breast problems related to lactation to be highly prevalent and described a sequence of symptoms which resembles the biomedical understanding of pathologies related to breastfeeding, ranging from breast engorgement (stasis) to inflammation (mastitis) and infection (breast abscess). The aetiology of disease, however, differed from biomedical notions as both women and guerisseurs distinguished between "natural" and "unnatural" causes of health problems related to breastfeeding. To prevent and treat such pathologies, women used a combination of traditional and biomedical therapies, depending on the perceived cause of illness. In general, however, a marked preference for traditional systems of care was observed. CONCLUSION: Health problems related to breastfeeding are perceived to be very common in rural Burkina Faso. Further epidemiological research to assess the actual prevalence of such pathologies is urgently needed to inform the design of adequate control measures, especially given the impact of mastitis on HIV vertical transmission. Our investigation into local illness concepts and health care seeking behaviour is useful to ensure that such measures be culturally sensitive. Further research into the efficacy of local customs and traditional healing methods and their effect on viral load in breast milk is also urgently needed.