DNA polymerase gamma variants and hepatotoxicity during maintenance therapy of childhood acute lymphoblastic leukemia: is there a causal relationship?

Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.

Transplacental transfer of SARS-CoV-2 antibodies: a cohort study.

The purpose of this study was to examine the transfer rate of SARS-CoV-2 IgG antibodies in pregnancy and newborns. Two Danish labor wards screened all women for SARS-CoV-2 by PCR upon arrival. Women (n = 99) with a SARS-CoV-2 PCR-positive nasopharyngeal (NP) swab or with a household member with a positive swab at labor or any time during pregnancy, or COVID-19 symptoms upon admission (November 2020 through August 2021), were included. Mother and infant were tested by NP swabs at delivery, and maternal and infant (umbilical cord) venous blood samples were collected. We obtained clinical information including previous PCR test results from the medical records. SARS-Cov-2 IgM and quantified IgG antibodies were measured by enzyme-linked immunosorbent assay and transfer ratios of IgG. We detected IgG antibodies in 73 women and 65 cord blood sera and found a strong correlation between SARS-CoV-2 IgG concentrations in maternal and umbilical cord sera (r = 0.9; p < 0.05). Transfer ratio was > 1.0 in 51 out of 73 (69%) infants and > 1.5 in 26 (35%). We found that transfer was proportional to time from a positive SARS-CoV-2 PCR NP swab to delivery (r = 0.5; p < 0.05). Transfer ratios of SARS-CoV-2 antibodies were associated with time from infection to delivery with transfer ratios of more than 1.0 in the majority of seropositive mother-infant dyads.

SARS-CoV-2 placentitis and severe pregnancy outcome after maternal infection: A Danish case series.

INTRODUCTION: SARS-CoV-2 infection during pregnancy may cause viral inflammation of the placenta, resulting in fetal demise even without fetal or newborn infection. The impact of timing of the infection and the mechanisms that cause fetal morbidity and mortality are not well understood. MATERIAL AND METHODS: To describe placental pathology from women with confirmed SARS-CoV-2 infection during pregnancy, a SARS-CoV-2 immunohistochemistry-positive placenta and late miscarriage, stillbirth, neonatal death, or medically indicated birth due to fetal distress. RESULTS: The triad of trophoblastic necrosis, inflammatory intervillous infiltrates, and increased perivillous fibrinoid deposition was present in all 17 placentas; the pregnancies resulted in eight stillbirths, two late miscarriages (19 and 21 weeks' gestation), and seven liveborn children, two of which died shortly after delivery. The severity of maternal COVID-19 was not reflected by the extent of the placental lesions. In only one case, SARS-CoV-2 was detected in lung tissue samples from the fetus. The majority events (miscarriage, stillbirth, fetal distress resulting in indicated birth, or livebirth, but neonatal death) happened shortly after maternal SARS-CoV-2 infection was diagnosed. Seven of eight sequenced cases were infected with the Delta (B.1.617.2) virus strain. CONCLUSION: We consolidate findings from previous case series describing extensive SARS-CoV-2 placentitis and placental insufficiency leading to fetal hypoxia. We found sparse evidence to support the notion that SARS-CoV-2 virus had infected the fetus or newborn.

Field Epidemiology and Public Health Microbiology training: capturing the alumni perspectives of the training's impact.

We present the findings from the European Programme for Intervention Epidemiology Training (EPIET) Alumni Network (EAN) Member Survey conducted in October to December 2021. The EAN consists of field epidemiologists (EPIET) and public health microbiologists (European Public Health Microbiology Training Programme (EUPHEM)) who stay connected after their 2-year fellowship. This active alumni network provides opportunities for career development, mentorship, knowledge exchange and sharing of best practices for community members, affiliated professionals and public health organisations in Europe. Overall, 281 of 732 members participated in the survey. Of the 192 European fellowship alumni respondents, 173 (90%) indicated that skills and competencies acquired during their fellowship improved performance in their role compared with their abilities before the fellowship. Reported skills and competencies that could be further strengthened included data management/analysis, communication, mathematical modelling and leadership/team management. The EAN Member Survey provides valuable feedback to the EAN, as well as the fellowship programme offices at the European Centre for Disease Prevention and Control (ECDC) and affiliated field epidemiology programmes. The COVID-19 pandemic was a stark reminder of how essential cross-border collaborations are for continued European health security. Maintaining and increasing the professional, well-trained workforce remains crucial for optimal response to infectious diseases and protection of public health.

Increase in invasive group A streptococcal infections and emergence of novel, rapidly expanding sub-lineage of the virulent Streptococcus pyogenes M1 clone, Denmark, 2023.

A highly virulent sub-lineage of the Streptococcus pyogenes M1 clone has been rapidly expanding throughout Denmark since late 2022 and now accounts for 30% of the new invasive group A streptococcal infections. We aimed to investigate whether a shift in variant composition can account for the high incidence rates observed over winter 2022/23, or if these are better explained by the impact of COVID-19-related restrictions on population immunity and carriage of group A Streptococcus.

Effects of germline DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia.

Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.

Evidence-based art in the hospital.

BACKGROUND: Evidence-based art is the investigation of art effects and art investigated for effects. In this study the evidence regarding patient preferences for art styles and effects of art in nonpsychiatric hospitals and outpatient departments was reviewed. METHODS: Results from original articles were retrieved by a scoping PubMed search and by browsing the internet using the terms "evidence based art", "evidence based design", "art and hospital" and "design and hospital", "art effect", "design effect", "landscape preference" and "abstract art figurative art". The quality of art was not operationalized as a criterion. RESULTS: Of the articles 7 original sources showed patient preference for natural scenes and figurative art, 2 studies showed no preference, 16 studies showed positive art effects on well-being and behavior and 5 studies showed a positive effect of nature pictures on measurable findings. CONCLUSION: Controversial results together with theoretical aspects suggest natural scenes in patient rooms and diverse art in public areas.

Pitfalls in Diagnosing Urinary Tract Infection in Children below the Age of 2: Suprapubic Aspiration vs Clean-Catch Urine Sampling.

PURPOSE: Reliable urine samples are of eminent importance when diagnosing urinary tract infections (UTIs) in children. Noninvasive procedures are convenient but likely to be contaminated. This study aimed to compare the diagnostic accuracy of urine samples obtained by the midstream clean-catch method (CCU) to urine obtained by suprapubic aspiration (SPA) and to evaluate the ability of urinary dipstick to predict true infection. MATERIALS AND METHODS: Retrospectively, data on children <2 years of age seen at our center for suspicion of UTI who had a CCU and a SPA performed the same day were included. Any growth in SPA was considered significant, whereas for CCU we tested 2 cutoff values of 104 and 105 CFU/ml, along with urinary dipstick results. RESULTS: A total of 223 children were included. Using a cutoff of ≥104 CFU/ml, 16.6% of the cohort (37 cases) would be misdiagnosed if relying only on CCU. Using ≥105 CFU/ml, the rate was 24.6% (55 cases). Evaluating leukocyte esterase on urinary dipstick, a large difference between using CCU (sensitivity 94.7%, specificity 14.4%) and SPA (sensitivity 78.9%, specificity 82.2%) became obvious. CONCLUSIONS: A large number of children will be misdiagnosed if relying on CCU specimens compared to SPA. Relying on a negative leukocyte esterase dipstick test to rule out a UTI is not sufficient in a child with high suspicion of such an infection. SPA is a safe procedure, and we thus recommend its use to avoid delay of treatment and unnecessary invasive followup investigations.

Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia.

Maintenance therapy containing methotrexate and 6-mercapto - purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6- fold higher cytosolic levels of thioguanine nucleotides than does 6- mercapto purine, we added low-dose 6-thioguanine to methotrexate/6- mercapto purine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the "Thiopurine Enhanced ALL Maintenance therapy" (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P<0.0001]), and with historical patients receiving standard methotrexate/6-mercapto - purine maintenance therapy (on average 272 fmol/mg DNA higher [95% confidence interval: 147-398; P<0.0001]). TEAM did not increase myelotoxicity or hepatotoxicity. In conclusion, TEAM is an innovative and feasible approach to improve maintenance therapy and results in higher DNA-TG levels without inducing additional toxicity. It may therefore be an effective strategy to reduce the risk of ALL relapse through increased DNA-TG. This will be tested in a randomized ALLTogether-1 substudy.

The serotype distribution of Streptococcus agalactiae (GBS) carriage isolates among pregnant women having risk factors for early-onset GBS disease: a comparative study with GBS causing invasive infections during the same period in Denmark.

BACKGROUND: We describe the serotype distribution of Streptococcus agalactiae (GBS) carriage isolates from women in labor and among GBS isolates causing invasive infections during the same period to see if the distribution of carriage serotypes reflects the GBS serotypes causing invasive diseases including early-onset disease (EOGBS). METHODS: Data on invasive isolates from 2019 including serotype, erythromycin and clindamycin susceptibility was retrieved from the Danish national reference laboratory, Statens Serum Institut. Carriage isolates were collected from women with risk factors for EOGBS enrolled at delivery at the maternity ward at a Danish University Hospital, first half of 2019. RESULTS: Among carriage isolates, the dominant serotype was IX (21 %) followed by serotype III (19 %). The resistance to erythromycin and clindamycin was 21 and 26 %, respectively. Among invasive GBS isolates, no case of EOGBS with serotype IX was detected but the distribution of serotypes were otherwise similar to the GBS carrier strains. The corresponding resistance to erythromycin and clindamycin was 23 and 15 %, respectively. Penicillin resistance was not detected among carriage nor invasive isolates. CONCLUSIONS: The distribution of serotypes among carriage and invasive GBS reflects the assumption that EOGBS occur following transmission of GBS from mother to newborn, with the exception of serotype IX.

Grandchildren's food workshop: Impact of an intergenerational cooking program on dietary habits, food courage, cooking skills and two-way interaction in Danish children and their grandparents.

BACKGROUND: Good nutrition is a key aspect of health. Cooking activities can improve dietary habits, cooking skills and food courage in terms of courage to cook and taste new foods, in individuals of all ages. However, targeting both grandchildren and grandparents at the same time through intergenerational cooking activities, is new. AIM: This paper aims to present the impact of intergenerational cooking activities on dietary habits, food courage, cooking skills and two-way interaction between young and old participants in The Grandchildren's Food Workshop. METHODS: In this observational pilot study, the Danish Heart Foundation's experimental cooking program for grandchildren and grandparents was developed and tested. The influence of the food workshop on the participants' dietary habits, food courage, cooking skills and two-way interaction was assessed by a before and after questionnaire. McNemar's and chi-squared tests were used to evaluate the effects. RESULTS: A total of 180 grandchildren (10 to 12 years) and 183 grandparents participated in The Grandchildren's Food Workshop. A total of 82 (46%) grandchildren (71% of which were girls) and 125 (68%) grandparents (83% of which were women) responded to the baseline and follow-up questionnaires. The impact on dietary habits and food courage was limited, while there was an impact on cooking skills in the grandchildren. The already good two-way interaction was unaltered. CONCLUSIONS: The findings indicate an impact on cooking skills among grandchildren participating in The Grandchildren's Food Workshop, while the impact on dietary habits, food courage and two-way interaction between age groups was limited. Further research, including more detailed dietary data, should explore the significance of an intergenerational approach.

The association between self-reported health status and adverse events: a comparison among coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI).

PURPOSE: While several studies have investigated clinical outcomes following coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI), studies investigating self-reported health and the association with adverse outcomes are limited. Thus, the aim was to investigate differences in health-related quality of life (HRQoL), anxiety and depression at discharge and the association with a composite endpoint of the first event of acute cardiac readmission, revascularisation or 1-year mortality among patients undergoing CABG vs. PCI. METHODS: Data from the national cohort study, DenHeart, were used, including measures of HRQoL; EuroQoL-5D-5L (EQ-5D Index Score and VAS) and HeartQoL (Global, Physical and Emotional), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and register-based follow-up. A total of 7000 patients were included (CABG n = 652, PCI n = 6348) (median age 65, 75% men). Cox Proportional Hazard models were performed among a propensity-matched population of responders (n = 520). RESULTS: HRQoL was significantly better among patients undergoing PCI vs. CABG, but with no differences in time to readmission or revascularisation. HRQoL, anxiety and depression were significantly associated with the risk of the composite endpoint among the PCI group (Hazard Ratio, HR (95% confidence intervals, CI) [EQ-5D index score 3.07 (1.67-5.67), EQ-5D VAS 0.97 (0.96-0.99), HeartQol Global 0.61 (0.38-0.95), HeartQol Emotional 0.56 (0.39-0.80), HADS-D ≥ 8 3.12 (1.61-6.01), HADS-A ≥ 8 2.08 (1.14-3.80)]. CONCLUSION: Patients undergoing PCI reported better HRQoL at discharge compared with patients undergoing CABG, whereas readmission rates were similar. Self-reported health was associated with the risk of adverse events among patients undergoing PCI, but not among patients undergoing CABG. CLINICAL TRIAL REGISTRATION: NCT01926145.

High prevalence of hepatitis C virus infection and low level of awareness among people who recently started injecting drugs in a cross-sectional study in Germany, 2011-2014: missed opportunities for hepatitis C testing.

BACKGROUND: In Germany, risk of hepatitis C virus (HCV) infection is highest among people who inject drugs (PWID). New injectors (NI) are particularly vulnerable for HCV-acquisition, but little is known about health seeking behaviour and opportunities for intervention in this group. We describe characteristics, HCV prevalence, estimated HCV incidence and awareness of HCV-status among NIs and missed opportunities for hepatitis C testing. METHODS: People who had injected drugs in the last 12 months were recruited into a cross-sectional serobehavioural study using respondent-driven sampling in 8 German cities, 2011-2014. Data on sociodemographic characteristics, previous HCV testing and access to care were collected through questionnaire-based interviews. Capillary blood was tested for HCV. People injecting drugs < 5 years were considered NI. RESULTS: Of 2059 participants with available information on duration of injection drug use, 232 (11% were NI. Estimated HCV incidence among NI was 19.6 infections/100 person years at risk (95% CI 16-24). Thirty-six percent of NI were HCV-positive (thereof 76% with detectable RNA) and 41% of those HCV-positive were unaware of their HCV-status. Overall, 27% of NI reported never having been HCV-tested. Of NI with available information, more than 80% had attended low-threshold drug services in the last 30 days, 24% were released from prison in the last 12 months and medical care was most commonly accessed in hospitals, opioid substitution therapy (OST)-practices, practices without OST and prison hospitals. CONCLUSION: We found high HCV-positivity and low HCV-status awareness among NI, often with missed opportunities for HCV-testing. To increase early diagnosis and facilitate treatment, HCV-testing should be offered in all facilities, where NI can be reached, especially low-threshold drug services and addiction therapy, but also prisons, hospitals and practices without OST.

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.

BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. METHODS: In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m2 once per day and methotrexate 20 mg/m2 once per week, targeted to a leucocyte count of 1·5-3·0 × 109 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. FINDINGS: Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/µg DNA increase, 95% CI 0·67-0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001). INTERPRETATION: Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. FUNDING: Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.

Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers.

BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. RESULTS: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). CONCLUSIONS: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy. PROCEDURE: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks. RESULTS: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 109 l-1 ) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01). CONCLUSIONS: PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. PROCEDURE: To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 109 /l. RESULTS: After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 109 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 109 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, rs  = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model. CONCLUSIONS: This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.

Prevalence of Chlamydia trachomatis infection in women, heterosexual men and MSM visiting HIV counselling institutions in North Rhine-Westphalia, Germany - should Chlamydia testing be scaled up?

BACKGROUND: Patients asking for a free anonymous HIV test may have contracted other sexually transmitted infections (STIs) such as Chlamydia trachomatis, yet Chlamydia prevalence in that population is unknown. This study aimed to assess the prevalence and factors associated with Chlamydia infection in patients seeking HIV testing at local public health authorities (LPHA) in order to evaluate whether Chlamydia testing should be routinely offered to them. METHODS: We conducted a cross-sectional study among patients (≥18 years) attending 18 LPHA in North Rhine-Westphalia from November 2012 to September 2013. LPHA collected information on participants' socio-demographic characteristics, sexual and HIV testing behaviours, previous STI history and clinical symptoms. Self-collected vaginal swabs and urine (men) were analysed by Transcription-Mediated Amplification. We assessed overall and age-stratified Chlamydia prevalence and 95 % confidence intervals (95 % CI). Using univariate and multivariable binomial regression, we estimated adjusted prevalence ratios (aPR) to identify factors associated with Chlamydia infection. RESULTS: The study population comprised 1144 (40.5 %) women, 1134 (40.1 %) heterosexual men and 549 (19.4 %) men who have sex with men (MSM); median age was 30 years. Chlamydia prevalence was 5.3 % (95 % CI: 4.1-6.8 %) among women, 3.2 % (95 % CI: 2.2-4.4) in heterosexual men and 3.5 % (95 % CI: 2.1-5.4) in MSM. Prevalence was highest among 18-24 year-old women (9 %; 95 % CI: 5.8-13) and heterosexual men (5.7 %; 95 % CI: 3.0-9.8 %), respectively. Among MSM, the prevalence was highest among 30-39 year-olds (4.4 %; 95 % CI: 1.9-8.5 %). Among those who tested positive, 76.7 % of women, 75.0 % of heterosexual men and 84.2 % of MSM were asymptomatic. Among women, factors associated with Chlamydia infection were young age (18-24 years versus ≥ 40 years, aPR: 3.0, 95 % CI: 1.2-7.8), having had more than 2 partners over the past 6 months (ref.: one partner, aPR: 2.1, 95 % CI: 1.1-4.0) and being born abroad (aPR: 1.9, 95 % CI: 1.0-3.5). Among heterosexual men, young age was associated with Chlamydia infection (18-24 years versus ≥ 40 years, aPR: 4.1, 95 % CI: 1.3-13). Among MSM, none of the variables were associated with Chlamydia infection. CONCLUSIONS: LPHA offering HIV tests should consider offering routine Chlamydia testing to women under 30 years. Women with multiple partners and those born abroad may also be considered for routine testing. Our results also suggest offering routine Chlamydia testing to heterosexual men under 25 years old. For MSM, we cannot draw specific recommendations based on our study as we estimated the prevalence of urethral Chlamydia infection, leaving out rectal and pharyngeal infections.

STI tests and proportion of positive tests in female sex workers attending local public health departments in Germany in 2010/11.

BACKGROUND: In Germany, local public health departments (LPHD) are required to offer low-threshold access to confidential counselling and testing for sexually transmitted infections (STI) for sex workers. We collected data from LPHD in Germany to estimate the number of performed STI tests and the proportion of positive STI tests among attending female sex workers (FSW) in order to formulate recommendations for improving STI testing and care for FSW in Germany. METHODS: We recruited LPHD across Germany to collect aggregated data on attending FSW between January 2010 and March 2011. Baseline characteristics, the number of attending FSW, STI tests (HIV, Chlamydia trachomatis, Neisseria gonorrhoea, syphilis and Trichomonas vaginalis) and the number of positive results were provided by participating LPHD. We described the number of STI tests per FSW visit and the proportion of positive test results, including interquartile range (IQR). We tested whether baseline characteristics of LPHD were associated with the proportion of positive test results. RESULTS: Overall, 28 LPHD from 14 of the 16 federal states reported 9284 FSW visits over the study period, with a median of 188 FSW visits (IQR 45-440) per LPHD. Overall, a median of 77.1% (IQR 60.7-88.0) of visiting FSW received a test for Neisseria gonorrhoea, followed by HIV (66.0%, IQR 47.9-86.8), Chlamydia trachomatis (65.4%, IQR 50.7-83.6) and syphilis (61.6, IQR 48.6-78.6). In total, 22,914 STI tests were performed. The proportion of positive tests was 3.1% (IQR 1.3-4.8), with the highest proportion of positive tests for Chlamydia trachomatis (6.8%, IQR 2.5-10.4), followed by Neisseria gonorrhoea (3.2%, IQR 0.0-5.3), Trichomonas vaginalis (3.0%, IQR 0.0-15.4), syphilis (1.1%, IQR 0.0-1.3) and HIV (0.2%, IQR 0.0-0.4). The proportion of positive tests varied between 0 and 13.9% between LPHD, with a higher variation of proportion of positive tests in LPHD with a smaller number of reported STI tests. CONCLUSIONS: Participating LPHD varied in terms of performed STI tests and FSW visits. The proportion of positive STI tests was low, but varied between LPHD. This variation likely reflects different testing strategies. Existing testing guidelines should be used by all LPHD to ensure high quality care for FSW.

High variability of HIV and HCV seroprevalence and risk behaviours among people who inject drugs: results from a cross-sectional study using respondent-driven sampling in eight German cities (2011-14).

BACKGROUND: People who inject drugs (PWID) are at increased risk of acquiring and transmitting HIV and Hepatitis C (HCV) due to sharing injection paraphernalia and unprotected sex. To generate seroprevalence data on HIV and HCV among PWID and related data on risk behaviour, a multicentre sero- and behavioural survey using respondent driven sampling (RDS) was conducted in eight German cities between 2011 and 2014. We also evaluated the feasibility and effectiveness of RDS for recruiting PWID in the study cities. METHODS: Eligible for participation were people who had injected drugs within the last 12 months, were 16 years or older, and who consumed in one of the study cities. Participants were recruited, using low-threshold drop-in facilities as study sites. Initial seeds were selected to represent various sub-groups of people who inject drugs (PWID). Participants completed a face-to-face interview with a structured questionnaire about socio-demographics, sexual and injecting risk behaviours, as well as the utilisation of health services. Capillary blood samples were collected as dried blood spots and were anonymously tested for serological and molecular markers of HIV and HCV. The results are shown as range of proportions (min. and max. values (%)) in the respective study cities. For evaluation of the sampling method we applied criteria from the STROBE guidelines. RESULTS: Overall, 2,077 PWID were recruited. The range of age medians was 29-41 years, 18.5-35.3 % of participants were female, and 9.2-30.6 % were foreign born. Median time span since first injection were 10-18 years. Injecting during the last 30 days was reported by 76.0-88.4 % of participants. Sharing needle/syringes (last 30 days) ranged between 4.7 and 22.3 %, while sharing unsterile paraphernalia (spoon, filter, water, last 30 days) was reported by 33.0-43.8 %. A majority of participants (72.8-85.8 %) reported incarceration at least once, and 17.8-39.8 % had injected while incarcerated. Between 30.8 and 66.2 % were currently in opioid substitution therapy. Unweighted HIV seroprevalence ranged from 0-9.1 %, HCV from 42.3-75.0 %, and HCV-RNA from 23.1-54.0 %. The implementation of RDS as a recruiting method in cooperation with low-threshold drop in facilities was well accepted by both staff and PWID. We reached our targeted sample size in seven of eight cities. CONCLUSIONS: In the recruited sample of mostly current injectors with a long duration of injecting drug use, seroprevalence for HIV and HCV varied greatly between the city samples. HCV was endemic among participants in all city samples. Our results demonstrate the necessity of intensified prevention strategies for blood-borne infections among PWID in Germany.