A phase II study of retifanlimab, a humanized anti-PD-1 monoclonal antibody, in patients with solid tumors (POD1UM-203).

BACKGROUND: POD1UM-203, an open-label, multicenter, phase II study, evaluated retifanlimab, a humanized monoclonal antibody targeting programmed cell death protein-1 (PD-1) in patients with selected solid tumors where immune checkpoint inhibitor therapies have previously shown efficacy. PATIENTS AND METHODS: Eligible patients (≥18 years) had measurable disease and included unresectable or metastatic melanoma, treatment-naive metastatic non-small-cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression (tumor proportion score ≥50%), cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (UC) with PD-L1 expression (combined positive score ≥10%), or treatment-naive locally advanced/metastatic clear-cell renal cell carcinoma (RCC). Retifanlimab 500 mg was administered intravenously every 4 weeks as a 30-min infusion. The primary endpoint was investigator-assessed overall response rate. RESULTS: Overall, 121 patients (35 melanoma, 23 NSCLC, 29 UC, 34 RCC) were enrolled and treated. The overall response rate [95% confidence interval (CI)] was 40.0% (23.9-57.9) in the melanoma cohort, 34.8% (16.4-57.3) in the NSCLC cohort, 37.9% (20.7-57.7) in the UC cohort, and 23.5% (10.7-41.2) in the RCC cohort. Median duration of response was 11.5 months (95% CI 2.2-not reached) in the UC cohort, and was not reached in the other cohorts. Retifanlimab safety was consistent with previous experience for PD-(L)1 inhibitors. CONCLUSIONS: Retifanlimab demonstrated durable antitumor activity in patients with melanoma, NSCLC, UC, or RCC. The efficacy and safety of retifanlimab were as expected for a PD-(L)1 inhibitor. These data support further study of retifanlimab in solid tumors.

The association between gut microbiome and growth in infants with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), pathophysiologic changes in the gastrointestinal tract lead to malnutrition and altered gut microbiome. Microbiome alterations have been linked to linear growth, gut inflammation and respiratory manifestations. Elucidating these gut microbiome alterations may provide insight into future nutritional management in CF. METHODS: Infants were followed for 12-months at four sites in the United States (US-CF) and Australia (AUS-CF). 16S rRNA gene sequencing was performed on longitudinal stool samples. Associations between microbial abundance and age, antibiotic prophylaxis, malnutrition, and breast feeding were evaluated using generalized linear mixed models. Taxonomic and predictive functional features were compared between groups. RESULTS: Infants with CF (N = 78) were enrolled as part of a larger study. AUS-CF infants had higher mean weight-for-age z-scores than US-CF infants (p = 0.02). A subset of participants (CF N = 40, non-CF disease controls N = 10) provided stool samples for microbiome analysis. AUS-CF infants had lower stool alpha diversity compared to US-CF infants (p < 0.001). AUS-CF infants had higher relative abundance of stool Proteobacteria compared to US-CF infants which was associated with antibiotic prophylaxis (p < 0.001). Malnutrition (weight-for-age <10th percentile) was associated with depleted Lactococcus (p < 0.001). Antibiotic prophylaxis (p = 0.002) and malnutrition (p = 0.012) were linked with predicted decreased activity of metabolic pathways responsible for short chain fatty acid processing. CONCLUSIONS: In infants with CF, gut microbiome composition and diversity differed between the two continents. Gut microbial diversity was not linked to growth. The relationship between malnutrition and antibiotic prophylaxis with reduced SCFA fermentation could have implications for gut health and function and warrants additional investigation.

Expiratory airflow at 7-8 years of age in children born extremely low birthweight from 14 years before to 14 years after the introduction of exogenous surfactant.

Background: It is unclear if expiratory airflow in survivors born extremely low birth weight (ELBW; 500-999 g) has improved after the introduction of exogenous surfactant into clinical practice in 1991. The primary aim of this study was to describe the changes in airflow at 7-8 years of age of survivors born ELBW in five discrete cohorts from 14 years before to 14 years after the introduction of exogenous surfactant into clinical practice. Methods: The cohorts comprised consecutive survivors born ELBW in 1977-82 and 1985-87 at the Royal Women's Hospital, Melbourne, and in 1991-92, 1997 and 2005 in the state of Victoria, Australia. Survival rates to 2-years of age for infants born ELBW in the state of Victoria rose from approximately 1-in-4 to 3-in-4 over the time of this study. Expiratory airflow measurements at 7-8 years included the forced expired volume in 1 s (FEV1), converted to z-scores for age, height, sex, and race. Findings: There were 596 ELBW participants with expiratory flow data, 280 (47%) of whom had bronchopulmonary dysplasia (BPD). Overall, there was little change in zFEV1 over the 28-year period (mean change per year; 0.003, 95% CI -0.010, 0.015, P = 0.67). There was, however, evidence of an interaction between BPD and year; zFEV1 in those who had BPD fell over time (mean change per year -0.019, 95% CI -0.037, -0.009, P = 0.035), whereas zFEV1 improved in those who did not have BPD (mean change per year 0.021, 95% CI 0.006, 0.037, P = 0.007). Interpretation: Contrary to recent evidence, expiratory airflow of children born ELBW has not improved with the introduction of surfactant, and may be deteriorating in those who had BPD. Funding: National Health and Medical Research Council (Australia); Victorian Government's Operational Infrastructure Support Program.

Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

The association between higher maternal pre-pregnancy body mass index and increased birth weight, adiposity and inflammation in the newborn.

BACKGROUND: Excess adiposity and adiposity-related inflammation are known risk factors for cardiovascular disease in adults; however, little is known regarding the determinants of adiposity-related inflammation at birth. OBJECTIVES: The aim of this study was to investigate the association between maternal pre-pregnancy BMI and newborn adiposity and inflammation. METHODS: Paired maternal (28-week gestation) and infant (umbilical cord) blood samples were collected from a population-derived birth cohort (Barwon Infant Study, n = 1074). Data on maternal comorbidities and infant birth anthropomorphic measures were compiled, and infant aortic intima-media thickness was measured by trans-abdominal ultrasound. In a selected subgroup of term infants (n = 161), matched maternal and cord lipids, high-sensitivity C-reactive protein (hsCRP) and maternal soluble CD14 were measured. Analysis was completed by using pairwise correlation and linear regression. Because of their non-normal distribution, pathology blood measures were log transformed prior to analysis. RESULTS: Maternal pre-pregnancy BMI was positively associated with increased birth weight (mean difference 17.8 g per kg m-2 , 95% CI 6.6 to 28.9; p = 0.002), newborn mean skin-fold thickness (mean difference 0.1 mm per kg m-2 , 95% CI 0.0 to 0.1; p < 0.001) and cord blood hsCRP (mean difference of 4.2% increase in hsCRP per kg m-2 increase in pre-pregnancy BMI, 95% CI 0.6 to 7.7%, p = 0.02), but not cord blood soluble CD14. Inclusion of maternal hsCRP as a covariate attenuated the associations between pre-pregnancy BMI and both newborn skin-fold thickness and cord blood hsCRP. CONCLUSION: Higher maternal pre-pregnancy BMI is associated with increased newborn adiposity and inflammation. These associations may be partially mediated by maternal inflammation during pregnancy.

Active safety monitoring of measles-mumps-rubella vaccine in the National Immunisation Programme of Sri Lanka

Objectives: This study was designed to report incidence and characteristics of selected adverse events following immunisation which have consistent causal association (AEFIc) with Measles-Mumps-Rubella (MMR) vaccination given at the age of one year in the National Immunisation Programme of Sri Lanka. Methods: The data presented here were obtained from a cohort event monitoring study. It was carried out in the Jaffna Regional Directorate of Health Services area from November 2012 to December 2014. A representative sample of 3002 infants who received MMR immunisation were actively followed up for adverse events (AE) using over the phone interviews, self-reporting, and home or hospital visits up to 45 days. All AEs were reviewed by two investigators independently in two step-wise processes to detect the AEFIc. Seven AEFIc were detected using standard case definitions and onset time limit criteria. They were subjected to further analysis to describe the incidence rates and characteristics. Results: Of the 2398 (80%) infants who completed follow up of 45 days, 1321 infants experienced 2621 AEFI. Of them 209 were classified as AEFIc. Incidence of AEFIc was 87/ 1000 immunisation. They were mainly nonserious and resolved completely. There were no fatal or life threatening AEFIs. Incidence per 1000 immunisations; allergic reactions 0.83, injection site reactions 4.58, fever100.4° F or lasting more than  3 days 9.59, macular papular rash 2.92, parotitis 2.92 and generalised convulsions 1.25. Conclusions: The MMR vaccine used in NIP of Sri Lanka had low incidence of AEFIc and were mainly non-serious in nature.

A coarse-grained model for assisting the investigation of structure and dynamics of large nucleic acids by ion mobility spectrometry-mass spectrometry.

Ion Mobility Spectrometry-Mass Spectrometry (IMS-MS) is a rapidly emerging tool for the investigation of nucleic acid structure and dynamics. IMS-MS determinations can provide valuable information regarding alternative topologies, folding intermediates, and conformational heterogeneities, which are not readily accessible to other analytical techniques. The leading strategies for data interpretation rely on computational and experimental approaches to correctly assign experimental observations to putative structures. A very effective strategy involves the application of molecular dynamics (MD) simulations to predict the structure of the analyte molecule, calculate its collision cross section (CCS), and then compare this computational value with the corresponding experimental data. While this approach works well for small nucleic acid species, analyzing larger nucleic acids of biological interest is hampered by the computational cost associated with capturing their extensive structure and dynamics in all-atom detail. In this report, we describe the implementation of a coarse graining (CG) approach to reduce the cost of the computational methods employed in the data interpretation workflow. Our framework employs a five-bead model to accurately represent each nucleotide in the nucleic acid structure. The beads are appropriately parameterized to enable the direct calculation of CCS values from CG models, thus affording the ability to pursue the analysis of larger, highly dynamic constructs. The validity of this approach was successfully confirmed by the excellent correlation between the CCS values obtained in parallel by all-atom and CG workflows.

Vitamin D insufficiency in the first 6 months of infancy and challenge-proven IgE-mediated food allergy at 1 year of age: a case-cohort study.

BACKGROUND: Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy. OBJECTIVE: To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year. METHODS: In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D3 (25(OH)D3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding. RESULTS: Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year. CONCLUSIONS: There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.

Resistance and utilisation pattern of antibacterial agents in outpatient settings in two Teaching Hospitals in Colombo.

OBJECTIVES: Antibacterial resistance (ABR) is a public threat. Sri Lanka is a country with limited surveillance of ABR in the community. The WHO methodology was adapted to identify ABR in outpatient settings (nonhospitalised patients) and its link to consumption of antibiotics. METHODS: It was a cross-sectional descriptive community based study to collect ABR data from Out Patient Department (OPD) of two leading Teaching Hospitals in Colombo district. The indicator organism Escherichia coli (E. coli) was obtained from the urine specimens of patients who were suspected to have urinary tract infections. Antibiotic susceptibility testing was performed for commonly used oral antibiotics using disc diffusion method. The antibiotic consumption aggregate data were collected from the OPD pharmacies of the said hospitals and expressed as Defined Daily Doses (DDD) per 1000 inhabitants per 1000 day. RESULTS: Of the 2183 urine samples, pathogenic E. coli was isolated in 9.3% (204), and 8% (n=16) of them were Extended Spectrum Beta Lactamase (ESBL) producers. E.coli was most resistant to ampicillin (85%), followed by nalidixic acid (58.5%), trimethoprim/sulphamethoxazole (47.1%), ciprofloxacin (46.2%), norfloxacin (43.7%) amoxicillin /clavulanic acid (36.3%) and nitrofurantoin (15%). Multi-drug resistance was seen in 44%. Amoxicillin was the most frequently consumed antibacterial agent (2.65 DDD per 1000 inhabitants per day). CONCLUSIONS: There is an alarmingly high antibiotic resistance in the non-hospitalised patients indicating high prevalence of E. coli resistance in the community.

Safety of live attenuated Japanese encephalitis vaccine given at the age of 9 months in National Immunisation Programme of Sri Lanka.

OBJECTIVES: This study was designed to describe the safety profile of the single dose live attenuated Japanese encephalitis vaccine (LJEV) SA-14-14-2 given at the age of 9 months in the National Immunisation programme of Sri Lanka. METHODS: cohort event monitoring (CEM) was conducted in the Jaffna district during November 2012 to January 2015. A representative sample of 3041 infants who received the LJEV at the age of 9 months was followed up actively over telephone interviews on days 1, 3, 14, 30 and 45 for adverse events (AE). Parents were encouraged to self-report in between these interviews. When an AE is notified, further clinical information was obtained through in-depth interviews and home/hospital visits to determine as an adverse event following immunisation (AEFI). Investigators independently reviewed each AEFI for consistent causal association with LJEV according to WHO causality assessment. RESULTS: Of the 2878 (94%) infants who completed the follow up of 14 days, 911 (32%) experienced 1423 AEFIs. Of them, 376 (26%) were identified as AEFI with consistent causal association to LJEV (AEFIc). Irritability (53/ 1000 doses administered) and fever ≥100.4° F (46/1000 doses administered) accounted for 41% and 35% of AEFIcrespectively. Majority of AEFI (940) were identified as inconsistent as there were alternate causes. Nineteen AEFIc in 14 infants were classified as serious since they led to hospitalisation. Of the 2392 (79%) infants who completed 45 days follow up, 1022 experienced 1804 AEFI during 15-45 days. Only 20 were identified as AEFIc. There were no reported fatal or life threatening AEs. CONCLUSIONS: LJEV administered to infants at 9 months was devoid of any significant safety concerns as most of the AEFIs were non-serious and resolved completely. CEM is a useful method for AEFI surveillance.

Medicines use in hospitalised children: current status and outcome after an intervention.

INTRODUCTION: Challenges in rational use of medicines (RUM) in children are different from that of adults. In Sri Lanka, data on RUM in children are limited. OBJECTIVE: To assess the current status and to investigate effectiveness of an intervention in improving RUM in children. METHODS: Non-randomised controlled before and after study design was employed. Study settings were one paediatric unit in two Teaching Hospitals one for intervention (IU) and the other as a control (CU) unit. After assessing the current status in both units, a combined intervention (one-time training and distribution of a paediatric formulary) was offered to IU and medicine use was re-assessed in both units three months and one year after intervention. Fourteen indicators (7 WHO and 7 developed by investigators) were employed in the assessment. Any improvement was analysed using percentage changes, Chi-square or t tests as appropriate. RESULTS: A total of 1134 charts, 735 (3197 medicines) in IU and 399 (1539 medicines) in CU were subjected to analysis. At base level, of the 14 indicators, 9 were assessed satisfactory in both units. Four could not be assessed without knowing the clinical setting. The remaining indicator, reason for prescribing was recorded for 48% and 76% of medicines respectively in IU and CU. After intervention, only three indicators, medicines that had the reason for prescription recorded in the patient records, children treated without regular medicines, and children received the recommended doses of paracetamol, showed favourable changes in three months and one year. Percentage of medicines written in abbreviation showed an undesirable increase in IU (6.9, 16.2, 29.6) which was higher than what was observed in CU (3.2, 13.5, 18.4). CONCLUSIONS: Passive interventions appear to be ineffective in improving RUM in children. In addition, general medicine use indicators seem to be insensitive to capture the true challenges in paediatric pharmacotherapy.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis

[{"text": "\"BACKGROUND:\r\nInfantile wheezing is a common problem, but there are no guidelines for the evaluation of infants with recurrent or persistent wheezing that is not relieved or prevented by standard therapies.\r\n\r\nMETHODS:\r\nAn American Thoracic Society-sanctioned guideline development committee selected clinical questions related to uncertainties or controversies in the diagnostic evaluation of wheezing infants. Members of the committee conducted pragmatic evidence syntheses, which followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The evidence syntheses were used to inform the formulation and grading of recommendations.\r\n\r\nRESULTS:\r\nThe pragmatic evidence syntheses identified few studies that addressed the clinical questions. The studies that were identified constituted very low-quality evidence, consisting almost exclusively of case series with risk of selection bias, indirect patient populations, and imprecise estimates. The committee made conditional recommendations to perform bronchoscopic airway survey, bronchoalveolar lavage, esophageal pH monitoring, and a swallowing study. It also made conditional recommendations against empiric food avoidance, upper gastrointestinal radiography, and gastrointestinal scintigraphy. Finally, the committee recommended additional research about the roles of infant pulmonary function testing and food avoidance or dietary changes, based on allergy testing.\r\n\r\nCONCLUSIONS:\r\nAlthough infantile wheezing is common, there is a paucity of evidence to guide clinicians in selecting diagnostic tests for recurrent or persistent wheezing. Our committee made several conditional recommendations to guide clinicians; however, additional research that measures clinical outcomes is needed to improve our confidence in the effects of various diagnostic interventions and to allow advice to be provided with greater confidence.\"", "_i": "en"}]

Surgery for endometriosis-associated infertility: do we exaggerate the magnitude of effect?

OBJECTIVE: Surgery remains the mainstay in the diagnosis and management of endometriosis. The number of surgeries performed for endometriosis worldwide is ever increasing, however do we have evidence for improvement of infertility after the surgery and do we exaggerate the magnitude of effect of surgery when we counsel our patients? The management of patients who failed the surgery could be by repeat surgery or assisted reproduction. What evidence do we have for patients who fail assisted reproduction and what is their best chance for achieving pregnancy? MATERIAL AND METHODS: In this study we reviewed the evidence-based practice pertaining to the outcome of surgery assisted infertility associated with endometriosis. Manuscripts published in PubMed and Science Direct as well as the bibliography cited in these articles were reviewed. Patients with peritoneal endometriosis with mild and severe disease were addressed separately. Patients who failed the primary surgery and managed by repeat or assisted reproduction technology were also evaluated. Patients who failed assisted reproduction and managed by surgery were also studied to determine of the best course of action. RESULTS: In patients with minimal and mild pelvic endometriosis, excision or ablation of the peritoneal endometriosis increases the pregnancy rate. In women with severe endometriosis, controlled trials suggested an improvement of pregnancy rate. In women with ovarian endometrioma 4 cm or larger ovarian cystectomy increases the pregnancy rate, decreases the recurrence rate, but is associated with decrease in ovarian reserve. In patients who have failed the primary surgery, assisted reproduction appears to be significantly more effective than repeat surgery. In patients who failed assisted reproduction, the management remains to be extremely controversial. Surgery in expert hands might result in significant improvement in pregnancy rate. CONCLUSION: In women with minimal and mild endometriosis, surgical excision or ablation of endometriosis is recommended as first line with doubling the pregnancy rate. In patients with moderate and severe endometriosis surgical excision also is recommended as first line. In patients who failed to conceive spontaneously after surgery, assisted reproduction is more effective than repeat surgery. Following surgery, the ovarian reserve may be reduced as determined by Anti Mullerian Hormone. The antral follicle count is not significantly reduced. In women with large endometriomas > 4 cm the ovarian endometrioma should be removed. In women who have failed assisted reproduction, further management remains controversial in the present time.

Feasibility of parental collected nasal swabs for virus detection in young children with cystic fibrosis.

BACKGROUND: The detrimental role of viruses has been well described in CF, although the pattern of virus infections has not been investigated in a longitudinal study. The primary aim was to determine the feasibility of fortnightly parent collected swabs in young children with CF. METHODS: Children under three years with CF were recruited. Nasal swabs were collected by parents every fortnight and during periods of symptoms over 12 months. Nasal swabs were posted and virus detected using real-time PCR. RESULTS: Only 27% of the patients completed the study to 10 months, although 98% of the swabs returned were adequate for analysis. Mould was observed growing on 23% of the returned swabs. There was no evidence to demonstrate relationships with symptoms and viruses, prolonged symptoms, prolonged shedding or patterns of virus infections. CONCLUSIONS: This study highlights the need to further investigate the role of viruses in children with CF using a robust method of frequent collection in children for a longitudinal study, with appropriate storage and shipping techniques to avoid mould growth or other potential contaminants.

MRI evidence of impaired CSF homeostasis in obesity-associated idiopathic intracranial hypertension.

BACKGROUND AND PURPOSE: Impaired CSF homeostasis and altered venous hemodynamics are proposed mechanisms for elevated pressure in IIH. However, the lack of ventricular expansion steered the focus away from CSF homeostasis in IIH. This study aims to measure intracranial CSF volumes and cerebral venous drainage with MR imaging to determine whether increased CSF volume from impaired CSF homeostasis and venous hemodynamics occur in obesity-related IIH. MATERIALS AND METHODS: Two homogeneous cohorts of 11 newly diagnosed pretreatment overweight women with IIH and 11 overweight healthy women were prospectively studied. 3D volumetric MR imaging of the brain was used to quantify CSF and brain tissue volumes, and dynamic phase contrast was used to measure relative cerebral drainage through the internal jugular veins. RESULTS: Findings confirm normal ventricular volume in IIH. However, extraventricular CSF volume is significantly increased in IIH (290 ± 52 versus 220 ± 24 mL, P = .001). This is even more significant after normalization with intracranial volume (P = .0007). GM interstitial fluid volume is also increased in IIH (602 ± 57 versus 557 ± 31 mL, P = .037). Total arterial inflow is normal, but relative venous drainage through the IJV is significantly reduced in IIH (65 ± 7% versus 81 ± 10%, P = .001). CONCLUSIONS: Increased intracranial CSF volume that accumulates in the extraventricular subarachnoid space provides direct evidence for impaired CSF homeostasis in obesity-associated IIH. The finding of larger GM interstitial fluid volume is consistent with increased overall resistance to cerebral venous drainage, as evident from reduced relative cerebral drainage through the IJV. The present study confirms that both impaired CSF homeostasis and venous hemodynamics coexist in obesity-associated IIH.

Bioinformatics meets parasitology.

The advent and integration of high-throughput '-omics' technologies (e.g. genomics, transcriptomics, proteomics, metabolomics, glycomics and lipidomics) are revolutionizing the way biology is done, allowing the systems biology of organisms to be explored. These technologies are now providing unique opportunities for global, molecular investigations of parasites. For example, studies of a transcriptome (all transcripts in an organism, tissue or cell) have become instrumental in providing insights into aspects of gene expression, regulation and function in a parasite, which is a major step to understanding its biology. The purpose of this article was to review recent applications of next-generation sequencing technologies and bioinformatic tools to large-scale investigations of the transcriptomes of parasitic nematodes of socio-economic significance (particularly key species of the order Strongylida) and to indicate the prospects and implications of these explorations for developing novel methods of parasite intervention.

A fat lot of good: balance and trends in fat intake in children with cystic fibrosis.

BACKGROUND: The fundamental nutritional treatment of a high fat diet for cystic fibrosis (CF) is established and essentially unchanged in the last 25 years. However, recent concerns have emerged regarding the potential risks of such a diet. We investigated the diets of children with CF to determine the source of energy, energy imbalance, and changing trends of fat intake. METHOD: In a prospective longitudinal study over 8 years at a single paediatric CF clinic three-day food diaries that included supplementary nutrition (SN) either as enteral feeds or oral nutritional supplements (ONS), were analysed annually. Influence of year on percent energy by type (fat, carbohydrate and protein) and on fat component: saturated (SFA); monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) was examined. RESULTS: 136 food diaries were analysed in 27 children (age range 1-18 years). 51 (37%) food diaries included SN (enteral feeds n=15 and ONS n=36). Mean energy intake was 1726 Kcals (oral diet alone) and 2245 Kcals (including SN). Percent energy from macronutrients did not change significantly over time (protein p=0.06; carbohydrate p=0.44; fat p=0.07) and remained within recommended levels. Mean caloric contribution from fat was 38.7% from oral diet alone and 37.8% including SN. Percent energy derived from SFA remained statistically unchanged (SFA p=0.57) but fell from MUFA (p=0.05) and PUFA (p=0.004). Mean SFA consistently contributed >134% (mean 158%) of reference nutrient intake and mean PUFA intake <100% (92%). CONCLUSION: Macronutrient intakes did not change significantly in our population of CF children, but there was a consistent imbalance of fat-sources with over-dependence on saturated fats which, in the context of increased survival in CF may potentially increase risk of cardiovascular disease. Further studies are needed to confirm our findings, investigate consequences of fat imbalance and guide clearer advice regarding appropriate proportions of sources of fat for CF patients.

A national survey of availability of key essential medicines for children in Sri Lanka.

OBJECTIVES: To investigate the availability of key essential medicines for children in Sri Lanka. METHODS: This national survey assessed the availability of 25 key essential medicines for children using the WHO/Health Action International medicine price methodology. Data were collected from a representative sample of 40 public hospitals (Outpatients Department pharmacies), 40 private and 8 'Rajya Osusala' (ROS) pharmacies. The hospitals and pharmacies were selected from 8 provinces using a multistage clustered approach to represent different levels of public hospitals. Descriptive statistics were used for analysis. RESULTS: The mean per cent availability of the basket of survey medicines was 52% in pubic hospitals when compared to 80% in private, and 88% in ROS pharmacies. teaching/general hospitals had better availability (mean per cent availability 62%) than district hospitals (54%), peripheral units (49%) and central dispensaries (45%). Availability of anti-infectives, anti-asthma medicines and oral liquid preparations of carbamazepine, iron, paracetamol, domperidone and ibuprofen was found to be less in public hospitals than private and ROS pharmacies. Availability in public hospitals similar to that of private and ROS pharmacies was only for paracetamol tablet, oral rehydration salt, vitamin C and chlorphenamine syrup. CONCLUSIONS: Key essential medicines for children were less available in public hospitals than in private and ROS pharmacies. This deprives children from access to effective and safe medicines more in the public hospitals than in the private sector or ROS.

IGF-1 protects against diabetic features in an in vivo model of Huntington's disease.

Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HTT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9 week-old and age-matched wild-type mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14 days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels.