Estimating the association between antibiotic exposure and colonization with extended-spectrum ß-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study.

OBJECTIVES: The aim of the study was to measure the impact of antibiotic exposure on the acquisition of colonization with extended-spectrum ß-lactamase-producing Gram-negative bacteria (ESBL-GNB) accounting for individual- and group-level confounding using machine-learning methods. METHODS: Patients hospitalized between September 2010 and June 2013 at six medical and six surgical wards in Italy, Serbia and Romania were screened for ESBL-GNB at hospital admission, discharge, antibiotic start, and after 3, 7, 15 and 30 days. Primary outcomes were the incidence rate and predictive factors of new ESBL-GNB colonization. Random forest algorithm was used to rank antibiotics according to the risk of selection of ESBL-GNB colonization in patients not colonized before starting antibiotics. RESULTS: We screened 10 034 patients collecting 28 322 rectal swab samples. New ESBL-GNB colonization incidence with and without antibiotic treatment was 22/1000 and 9/1000 exposure-days, respectively. In the adjusted regression analyses, antibiotic exposure (hazard ratio (HR) 2.38; 95% CI 1.29-4.40), age 60-69 years (HR 1.19; 95% CI 1.05-1.34), and spring season (HR 1.25; 95% CI 1.14-1.38) were independently associated with new colonization. Monotherapy ranked higher als combination therapy in promoting ESBL-GNB colonization. Among monotherapy, cephalosporins ranked first followed by tetracycline (second), macrolide (fourth) and cotrimoxazole (seventh). Overall the ranking of cephalosporins was lower when used in combination. Among combinations not including cephalosporins, quinolones plus carbapenems ranked highest (eighth). Among sequential therapies, quinolones ranked highest (tenth) when prescribed within 30 days of therapy with cephalosporins. CONCLUSIONS: Impact of antibiotics on selecting ESBL-GNB at intestinal level varies if used in monotherapy or combination and according to previous antibiotic exposure. These finding should be explored in future clinical trials on antibiotic stewardship interventions. CLINICAL TRIAL REGISTRATION: NCT01208519.

Children with facial morphoea managing everyday life: a qualitative study.

BACKGROUND: Facial morphoea is a chronic inflammatory skin disorder, typically presenting in childhood and adolescence, which can be disfiguring, and which has been suggested to cause mild-to-moderate impairment in quality of life. OBJECTIVES: To explore the everyday experiences of children with facial morphoea by examining the psychosocial impact of living with facial morphoea and how children and their families manage its impact. METHODS: We used a qualitative, social constructionist approach involving focus groups, in-depth interviews and drawing activities with 10 children with facial morphoea aged 8-17 years and 13 parents. Interpretive thematic analysis was utilized to examine the data. RESULTS: Children and parents reported on the stress of living with facial morphoea, which was related to the lack of knowledge about facial morphoea and the extent to which they perceived themselves as different from others. Self-perceptions were based on the visibility of the lesion, different phases of life transitions and the reactions of others (e.g. intrusive questioning and bullying). Medication routines, and side-effects such as weight gain, added to the stress experienced by the participants. To manage the impact of facial morphoea, children and their parents used strategies to normalize the experience by hiding physical signs of the illness, constructing explanations about what 'it' is, and by connecting with their peers. CONCLUSIONS: Understanding what it is like to live with facial morphoea from the perspectives of children and parents is important for devising ways to help children with the disorder achieve a better quality of life. Healthcare providers can help families access resources to manage anxiety, deal with bullying and construct adequate explanations of facial morphoea, in addition to providing opportunities for peer support.

Rotavirus and other Diarrheal Disease in a Birth Cohort from Southern Indian Community.

OBJECTIVE: To describe the incidence, severity and etiology of diarrheal disease in infants and young children residing in an urban slum community in Southern India. SETTING: Three contiguous urban slums in Vellore, Tamil Nadu. PARTICIPANTS: 452 children participating in a birth cohort study on diarrheal disease; 373 completed three years of follow-up. OUTCOME MEASURES: Diarrheal incidence (obtained by twice-weekly home visits) and severity (assessed by the Vesikari scoring system), and etiological agents associated with diarrhea (through examination of stool specimens by bacteriologic culture, rotavirus enzyme immunoassay, PCR for norovirus and microscopy for parasites). RESULTS: A total of 1856 diarrheal episodes were reported in 373 children. The overall incidence rate of diarrhea was 1.66 episodes per child year for three years, with 2.76 episodes per child year in infancy. The incidence peaked during the months of July and August. Severe diarrhea formed 8% of the total episodes. Rotavirus was the most common pathogen detected, being identified in 18% of episodes. Good hygiene status resulted in 33% protection against moderate-to-severe diarrhea. CONCLUSIONS: This study highlights the burden of diarrheal disease and the important etiological agents of childhood diarrhea in Southern India. Promotion of hygienic behavior through health education may help reduce diarrheal incidence in this and similar communities.

The impact of bariatric surgery on quality of life: a systematic review and meta-analysis.

This study aims to review the obesity literature in order to assess the impact of bariatric surgery on quality of life and the between-study variation by examining the standardized mean magnitude of effect in change in the levels of quality of life. The following databases EMBASE, PubMed, PsycINFO, CINAHL, the Cochrane Library and Web of Science were systematically searched for studies examining change in quality of life in adults receiving bariatric surgery for obesity. Seventy-two studies were included with a total of 9,433 participants treated for obesity with bariatric surgery. The average impact of bariatric surgery on quality of life corresponded to an effect size of 0.88 (95% CI: 0.80-0.96), indicating that bariatric surgery has a significant positive influence on quality of life in general. The impact varied considerably across studies with bariatric surgery showing a significantly greater positive influence on physical quality of life compared to mental quality of life. Bariatric surgery is effective in improving quality of life, especially when looking at physical well-being. Greater focus on the psychological well-being of the person undergoing surgery for obesity may lead to a better post-surgery prognosis for more people.

Investigation of a hepatitis A outbreak in children in an urban slum in Vellore, Tamil Nadu, using geographic information systems.

BACKGROUND & OBJECTIVE: An outbreak of symptomatic viral hepatitis in children less than 10 yr of age in Vellore, south India, was investigated and the disease pattern studied using serological and epidemiological methods, supplemented by geographic information systems (GIS) mapping. METHODS: Three cases of hepatitis A were identified during routine surveillance in a birth cohort House-to-house visits were undertaken to identify other symptomatic cases and samples collected for anti- HAV IgM, ELISA testing. All cases and controls were mapped and geo-referenced using Arc View GIS 3.3. Spatial clustering was investigated using SaTScan 7.0.1 software. Drinking water sources were tested for coliform counts with the most probable number technique. RESULTS: Of the 965 children surveyed, 26 (2.78%) had jaundice between February to July 2006. From the 26 patients, 11 (42.3%) blood samples were obtained and tested for anti-HAV IgM; 10 (90.9%) were found to be positive. Water analysis showed high coliform counts in all samples. No spatial clustering of cases could be detected. INTERPRETATION & CONCLUSION: The outbreak was identified because of the symptomatic presentation of the cases. Our study highlighted the increasing detection of symptomatic children with hepatitis A virus infection. Water sources in the area were contaminated and may have served as the source of infection. The lack of clustering in GIS analysis could be due to the common water source.

Infant morbidity in an Indian slum birth cohort.

OBJECTIVE: To establish incidence rates, clinic referrals, hospitalisations, mortality rates and baseline determinants of morbidity among infants in an Indian slum. DESIGN: A community-based birth cohort with twice-weekly surveillance. SETTING: Vellore, South India. SUBJECTS: 452 newborns recruited over 18 months, followed through infancy. MAIN OUTCOME MEASURES: Incidence rates of gastrointestinal illness, respiratory illness, undifferentiated fever, other infections and non-infectious morbidity; rates of community-based diagnoses, clinic visits and hospitalisation; and rate ratios of baseline factors for morbidity. RESULTS: Infants experienced 12 episodes (95% confidence interval (CI) 11 to 13) of illness, spending about one fifth of their infancy with an illness. Respiratory and gastrointestinal symptoms were most common with incidence rates (95% CI) of 7.4 (6.9 to 7.9) and 3.6 (3.3 to 3.9) episodes per child-year. Factors independently associated with a higher incidence of respiratory and gastrointestinal illness were age (3-5 months), male sex, cold/wet season and household involved in beedi work. The rate (95% CI) of hospitalisation, mainly for respiratory and gastrointestinal illness, was 0.28 (0.22 to 0.35) per child-year. CONCLUSIONS: The morbidity burden due to respiratory and gastrointestinal illness is high in a South Indian urban slum, with children ill for approximately one fifth of infancy, mainly with respiratory and gastrointestinal illnesses. The risk factors identified were younger age, male sex, cold/wet season and household involvement in beedi work.

Polymerase chain reaction in the detection of an 'outbreak' of asymptomatic viral infections in a community birth cohort in south India.

Asymptomatic enteric infections are important where sequelae or protection from subsequent illness is an outcome measure. The use of reverse transcription-polymerase chain reaction (RT-PCR) to identify asymptomatic enteric infections in a birth cohort followed for rotaviral infections in a south Indian urban slum is reported. Of 1191 non-diarrhoeal samples from 371 children collected in May-June 2003, 22 (1.9%) were positive by ELISA. A total of 147 (40.6%) of 362 samples tested by VP6 RT-PCR were positive. In those samples that could be typed, a high diversity of G types including G1, G2, G4, G8, G9 and G10, and a high proportion (34.4%) of mixed infections were detected. Noroviruses were identified in 6/28 (21.4%) samples tested. The identification of infections undetectable by conventional techniques indicates the importance of the use of sensitive diagnostic techniques in research studies. Asymptomatically infected children may also act as a source of infection for other susceptible hosts.

Clinical features & risk factors associated with cryptosporidiosis in HIV infected adults in India.

BACKGROUND & OBJECTIVE: Cryptosporidiosis is a leading cause of protracted, life threatening diarrhoea in HIV infected patients. Although data on prevalence are available for Indian patients, no information on risk factors for transmission exists. We therefore undertook this study to identify risk factors for transmission of cryptosporidiosis in HIV infected adults. METHODS: Both symptomatic (diarrhoeal) and asymptomatic HIV infected patients were screened for cryptosporidiosis. All Cryptosporidium spp. positive cases were enrolled in the study and interviewed to record socio-demographic information, water supply and animal contact. Data were analysed to study clinical features and potential association with species and genotype. RESULTS: Of the 28 cryptosporidial infections identified on screening 111 HIV positive patients with diarrhoea, 10 (35.7%) had chronic diarrhoea, 14 (50%) had associated fever and 8 (28.6%) had nausea. Symptomatic patients had a significantly higher number of co-infections with other enteric parasites (P=0.04) than 20 asymptomatics of 423 HIV positive individuals screened. Eleven of 17 (64%) patients with potentially zoonotic infections had diarrhoea. Patients with zoonotic species (64%) also tended to have fever more frequently than those infected with C. hominis (58%). Association between area of residence, rural or urban, water source and contact with animals and acquisition of cryptosporidiosis was not statistically significant. INTERPRETATION & CONCLUSION: Cryptosporidiosis is an important cause of morbidity in HIV infected individuals in India, resulting in chronic diarrhoea. Risk factors for potentially zoonotic transmission of cryptosporidiosis were described in this study, but larger studies need to be done for a clearer understanding of the transmission dynamics of different cryptosporidial species in developing countries.

Cutting edge: introduction of an endopeptidase cleavage motif into a determinant flanking region of hen egg lysozyme results in enhanced T cell determinant display.

The choice of which determinants of a whole Ag will be presented on cell surface MHC class II molecules after uptake and processing by APC is the result of the interplay between structural characteristics of the Ag and the processing machinery of the APC. In this study, we demonstrate that introduction of a dibasic motif adjacent to a subdominant determinant enhances the presentation of this determinant from the whole molecule. This is the first report showing that a single amino acid substitution in a whole Ag, designed to introduce an endopeptidase recognition site, enhances display of class II-restricted determinants, most likely by creating a peptide chain cleavage in the antigenic molecule. Our findings have important implications for the understanding of immunodominance and for vaccine design.

Clinical significance of cytogenetic findings at diagnosis and in remission in childhood and adult acute lymphoblastic leukemia: experience from India.

We report cytogenetic findings in 114 patients of acute lymphoblastic leukemia (ALL), which includes 78 children (< or = 15 years) and 36 adults (16-60 years). Chromosome aberrations were detected in 109 (95%) cases. A lower frequency of hyperdiploidy (15%) in children and a higher frequency of hypodiploidy both in children (38.4%) and adults (44.4%) were found, in contrast to literature. Translocations were detected in one third of adult and pediatric cases. The incidence of t(9;22) was comparatively low in adults (7.7%). Frequency of t(1:19) was also low in overall ALL cases. Various other recurrent abnormalities such as del(6q), abn(11q23), i(9p), abn(12q13), del(7q), and i(17q) were seen in our cases; a striking difference in the incidence of del(6q) (41%) and abn(11q23) (30%) was found in our series versus reported literature. Ploidy distribution indicated association of pseudo- and hypodiploidy with B-lineage, and hypodiploidy with T-lineage in children. The occurrence of del(6q) was more frequent in pediatric ALL with highly aberrant pattern and also with lymphadenopathy. Abn(11q23) was found to be early-B and pre-B specific. Kaplan-Meier analysis of overall survival revealed prognostic value of sex, FAB, immunophenotype, and cytogenetic findings. Females and T-ALL patients had a better prognosis, whereas males and B-ALL patients had poor outcome in overall and pediatric age groups. Prognostic evaluation of cytogenetics indicated translocations as an independent high-risk predictor in childhood (P < 0.008) and adult ALL (P < 0.01). Childhood ALL with t(8;14) and t(4;11) and adults with t(9;22) had poor survival. Cytogenetics of remission marrows demonstrated disappearance of abnormal clones in 31.4%, and expansion in normal clones in 50% of patients. Persistence of original clones and development of new clones were observed in 20% and 33% of patients, respectively; whereas karyotype evolution was identified in 10% of patients. The prognostic significance of cytogenetic findings at diagnosis, and differential cytogenetic response in so-called clinical remission in our study indicated the utmost need for more intensive therapy for eradication of resistant clones, and necessity of sequential cytogenetic follow-up in these patients for identification of minimal residual disease.

Acute promyelocytic leukemia: all-trans retinoic acid (ATRA) along with chemotherapy is superior to ATRA alone.

This study was conducted to compare the results of treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid alone (ATRA) or a combination therapy of ATRA followed by chemotherapy. Forty-three patients treated between February 1992 and February 1996 were included in this study. Eighteen patients were treated with ATRA alone and 25 patients were treated with ATRA followed by chemotherapy. The cytogenetic analysis was done in 41 patients at presentation, following treatment, and at follow-up. A complete response (CR) was achieved in 13 (72%) patients on ATRA and 19 (76%) on ATRA followed by chemotherapy. Eleven of 13 patients with response to ATRA alone relapsed with median survival of eight months (range, 1 to 28). One patient died of hepatitis in CR and one patient is alive 2 years after diagnosis. In the combination therapy arm, 10 patients are in CR with a median follow-up of 22 months (range, 6 to 56 months). After achieving a CR, four patients died due to infections during chemotherapy therapy, and only 5 of 19 patients have relapsed. Major cytogenetic response was seen in 8 of the 10 patients in whom cytogenetic data was available after treatment with ATRA at the time of remission. Similarly, 13 of 15 for whom data was available showed a major cytogenetic response after treatment with ATRA plus chemotherapy. Prior to relapse, 80% of the patients had an increase in the percentage of t(15;17) cells in the marrow. Patients with a complete hematological response but no cytogenetic response relapsed within six months. Ten patients died prior to response evaluation. Two patients who received ATRA died of retinoic acid syndrome, one of pneumonia, and one of intracranial hemorrhage. Of the six patients on ATRA and chemotherapy, four died of retinoic acid syndrome (RAS), one of intracranial hemorrhage, and one of left ventricular failure. Only one patient is alive at 24 months following treatment with ATRA alone. The relapse-free survival is 42% at four years for patients treated with ATRA followed by chemotherapy. This trial is a historical comparison of ATRA alone and ATRA with subsequent combination chemotherapy. Nonetheless, the trial shows a significant improvement in the event free survival of patients receiving chemotherapy as consolidation following ATRA.

Malignant transformation of Syrian hamster embryo (SHE) cells in culture by malachite green: an agent of environmental importance.

Malachite green (MG), consisting of green crystals with a metallic lustre, is very soluble in water and is highly cytotoxic to mammalian cells in culture and also acts as a liver tumour promoter. In view of its industrial importance and possible exposure to human beings, MG poses a potential environmental health hazard. Accordingly, we have studied the effect of MG on the formation of free radicals using Electron Spin Resonance (ESR) analysis with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent. ESR analysis showed formation of reactive free radicals during exposure of MG to Syrian hamster embryo (SHE) cells. As per mechanism-based toxicology in cancer risk assessment, the chemicals that have the potential to be metabolized to active free radical species could be human cancer hazards. So, we have investigated the effect of MG on the formation of Type II and Type III morphologically transformed foci using SHE cell transformation assay. MG induced dose related transformed foci. Some of these transformed foci were taken out using selective trypsinisation and established immortal cell lines. One of these immortal cell lines was characterized extensively. This immortal cell line showed enhanced DNA synthesis in the form of BrdU incorporation, increased presence of proliferating cell nuclear antigen (PCNA), bcl-2 and p53 proteins by immunohistochemistry. When these immortal cells were injected subcutaneously into nude mice, they developed tumors which were transplantable and histopathologically sarcomas. The present studies indicate that MG could be a potential candidate for two year chemical carcinogenesis rodent bioassays.

Cytogenetic studies in patients from India with T-acute lymphoblastic leukemia.

Cytogenetic analysis was performed in 30 patients with T cell acute lymphoblastic leukemia (11 adults, 19 children) at initial presentation and analysis was also repeated in clinical and hematological remission in 15 patients. At initial presentation, chromosomal abnormalities were detected in 27 cases (90%) and hypodiploidy was detected in 19 patients (63.3%), followed by pseudodiploidy in six patients (20%) and hyperdiploidy in two patients (6.6%). Other karyotypic abnormalities detected were deletion 6q (40%), deletion 11 q (16.6%), deletion 7q (10%), abnormalities of chromosome 9 in (13.3%) and translocation t(11;14)(p13;q11) in 6.6% and der(12)t(12;?)(p13;?) in (3.3%). In complete remission, nine out of 15 cases (60%) showed chromosomal aberrations. Original abnormalities were detected in two cases (13.3%) and new abnormalities were detected in seven cases (46.6%).

All-trans-retinoic acid (ATRA): pediatric acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloblastic leukemia (AML). In this report, we present the clinical features, management, and outcome of pediatric patients with APL treated with all-trans-retinoic acid (ATRA). Of 52 newly diagnosed cases of APL between February 1992 and December 1996, 15 were in the pediatric age group (younger than 15 years). Four patients were treated with ATRA alone and 11 were allocated to receive ATRA followed by chemotherapy. Eighty-six percent of the patients achieved a complete response. The patients who received ATRA alone as maintenance therapy had relapses with a median duration of remission of 8 months (range 6-12). The patients who received ATRA, followed by consolidation chemotherapy, had a prolonged duration of remission, with a median of 20 months (range 13-28). In addition, rapid correction of coagulopathy was observed in these patients. The median duration for correction of coagulopathy was 7 days (range 5-11) and the median duration for recovery from neutropenia after chemotherapy was 10 days (range 7-20). Two major side effects of ATRA were hyperleukocytosis and retinoic acid syndrome. Significantly prolonged disease-free survival was seen in patients who received ATRA with chemotherapy. APL is not uncommon in the pediatric age group. ATRA was well-tolerated by these patients. Consolidation with chemotherapy helps in prolonging the disease-free survival in patients with APL in comparison to treatment with ATRA alone.

Secondary ANLL with t(11;19)(q23;p13) following etoposide and cisplatin for ovarian germ cell tumor.

This is a case report of a ten year old girl with ovarian germ cell tumor who was successfully treated with BEP chemotherapy. She developed acute myloid leukemia, AML-M5 with t(11;19)(q23;p13), 29 months after being off therapy. She received a cumulative dose of 2000 mg/m2 of etoposide and 400 mg/m2 of cisplatin. The association of etoposide and therapy related leukemia is reviewed.

Calla positive acute lymphoblastic leukemia after etoposide-based therapy for Ewing's sarcoma.

This is an unusual and interesting case report concerning a 10 year old boy with an initial diagnosis of Ewing's sarcoma of the right tibia. He was successfully treated with a chemotherapy regimen consisting of vincristine, cyclophosphamide (cumulative dose 7200 mg/m2), doxorubicin, etoposide (cumulative dose 2700 mg/m2) and cisplatin and local radiotherapy to the tibia. After an interval of 37 months he developed CALLA positive acute lymphoblastic leukemia with 11q23 chromosomal abnormality. The possible roles of etoposide and cyclophosphamide are discussed.

Cytogenetic studies on patients of acute lymphoblastic leukemia Burkitt's type with (8;14) & (14;18) translocations.

Eight patients with acute lymphoblastic leukemia of Burkitt's type (ALL-L3) and two patients with Burkitt's lymphoma (BL) were subjected for cytogenetic studies. Translocation (8;14)(q24;q32) was present in nine (90%) patients; seven patients of ALL-L3 and two of BL. One ALL-L3 patient revealed t(14;18)(q32;q21) in 100 per cent metaphases. Additional clonal chromosomal anomalies present in these patients were deletion (6q) (40%) and trisomy 21(20%). The occurrence of t(8;14)(q24;q32) in ALL-L3 and BL patients in our series supports the association of t(8;14) with ALL-L3 and Burkitt's lymphoma.

Rhabdomyosarcoma. A cytogenetically interesting case report.

Chromosomal analysis was performed on the tumor tissue in a case of ocular rhabdomyosarcoma. Cytogenetic analysis revealed multiple clonal abnormalities. Derivative(5)t(1;5)(q21;q35) and t(2;11) (q21;q23) were present in all the metaphases analyzed (100%). Translocation(1;19)(q21;q13) was observed in 61% of the metaphases. Other clonal abnormalities present included +i(6p)(85%),i(17q)(38%),18q+(57%), 4p+ (38%), loss of the Y chromosome (33%), and presence of double minutes (12.8%).