Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189.

BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.

BACKGROUND: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). CONCLUSIONS: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors.

BACKGROUND: While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. PATIENTS AND METHODS: Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. RESULTS: We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. CONCLUSIONS: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

Unique volatolomic signatures of TP53 and KRAS in lung cells.

BACKGROUND: Volatile organic compounds (VOCs) are potential biomarkers for cancer detection in breath, but it is unclear if they reflect specific mutations. To test this, we have compared human bronchial epithelial cell (HBEC) cell lines carrying the KRAS(V12) mutation, knockdown of TP53 or both with parental HBEC cells. METHODS: VOC from headspace above cultured cells were collected by passive sampling and analysed by thermal desorption gas chromatography mass spectrometry (TD-GC-MS) or sensor array with discriminant factor analysis (DFA). RESULTS: In TD-GC-MS analysis, individual compounds had limited ability to discriminate between cell lines, but by applying DFA analysis combinations of 20 VOCs successfully discriminated between all cell types (accuracies 80-100%, with leave-one-out cross validation). Sensor array detection DFA demonstrated the ability to discriminate samples based on their cell type for all comparisons with accuracies varying between 77% and 93%. CONCLUSIONS: Our results demonstrate that minimal genetic changes in bronchial airway cells lead to detectable differences in levels of specific VOCs identified by TD-GC-MS or of patterns of VOCs identified by sensor array output. From the clinical aspect, these results suggest the possibility of breath analysis for detection of minimal genetic changes for earlier diagnosis or for genetic typing of lung cancers.

Recent trends in the epidemiology of shigellosis in Israel.

We provide an update on the epidemiology of shigellosis in Israel using data generated by a sentinel laboratory-based surveillance network for the period 1998-2012. The average annual incidence of culture-proven shigellosis was 97/100 000. We estimated that each case of shigellosis accounted for 25 cases in the community indicating the high burden of disease. Orthodox Jewish communities, living in highly crowded conditions and with a high number of children aged <5 years were the epicentre of country-wide biennial propagated epidemics of S. sonnei shigellosis. S. flexneri was the leading Shigella serogroup in Israeli Arabs. S. flexneri 2a and S. flexneri 6 alternated as the most common serotypes. Both S. sonnei and S. flexneri isolates showed high rates of resistance to ampicillin and trimethoprim/sulfamethoxazole and very low rates of resistance to quinolones and third-generation cephalosporins. Shigellosis due to S. sonnei conferred 81% (95% confidence interval 69-89) protection against the homologous Shigella serotype when epidemic exposure re-occurred 2 years later. These data are of value in the process of Shigella vaccine development.

The use of ultrasound for the assessment of enthesitis in patients with spondyloarthritis.

Seronegative spondyloarthritis (SpA) represents a group of diseases that share certain genetic, clinical, and radiographic features. Enthesitis, inflammation at the site of tendon insertion into the bone, involving both the axial and the peripheral joints, is an important sign of SpA. Clinical diagnosis of enthesitis, however, is neither sensitive nor specific; thus, the diagnosis of enthesitis often relies on typical abnormalities in imaging studies. Due to its low costs and availability, ultrasound is emerging as the preferred technique for detection of enthesitis for both clinical and research purposes. Ultrasonographic features of enthesitis include tendon hypoechogenicity and thickening, calcifications, bone erosions, and Doppler signal. Several semi-quantitative scoring systems have been developed to quantify ultrasonographic abnormalities of the entheses. These methods have been used for early diagnosis and classification of SpA as well as for monitoring response to treatment.

Recent trends in the epidemiology of non-typhoidal Salmonella in Israel, 1999-2009.

The aim of the present study was to assess the recent trends in the epidemiology of non-typhoid Salmonella in Israel using a sentinel laboratory-based surveillance network. Between 1999 and 2009, 8758 Salmonella stool isolates were reported by five sentinel laboratories. There was a significant decrease in the incidence rate of Salmonella isolates from 70·5/100,000 in 1999 to 21·6/100,000 in 2005 followed by a slight increase to 30·3/100,000 in 2009. Of all Salmonella, 64·3% were isolated from children in the 0-4 years age group. Up to 2008, S. Enteritidis was the most prevalent serotype and in 2009 S. Infantis emerged as the most common Salmonella serotype. The decrease in the incidence of S. Enteritidis and S. Typhimurium and increase in S. Infantis among humans were associated with a similar trend among breeding flocks, which followed significant preventive interventions conducted against S. Enteritidis and S. Typhimurium infections in poultry. Tight surveillance and education of food handlers and consumers should be enhanced to reduce the foodborne transmission of Salmonella in Israel.

Degenerative lumbar spinal stenosis and lumbar spine configuration.

As life expectancy increases, degenerative lumbar spinal stenosis (DLSS) becomes a common health problem among the elderly. DLSS is usually caused by degenerative changes in bony and/or soft tissue elements. The poor correlation between radiological manifestations and the clinical picture emphasizes the fact that more studies are required to determine the natural course of this syndrome. Our aim was to reveal the association between lower lumbar spine configuration and DLSS. Two groups were studied: the first included 67 individuals with DLSS (mean age 66 ± 10) and the second 100 individuals (mean age 63.4 ± 13) without DLSS-related symptoms. Both groups underwent CT images (Philips Brilliance 64) and the following measurements were performed: a cross-section area of the dural sac, vertebral body dimensions (height, length and width), AP diameter of the bony spinal canal, lumbar lordosis and sacral slope angles. All measurements were taken at L3 to S1. Vertebral body lengths were significantly greater in the DLSS group at all levels compared to the control, whereas anterior vertebral body heights (L3, L4, L5) and middle vertebral heights (L3, L5) were significantly smaller in the LSS group. Lumbar lordosis, sacral slope and bony spinal canal were significantly smaller in the DLSS compared to the control. We conclude that the size and shape of vertebral bodies and canals significantly differed between the study groups. A tentative model is suggested to explain the association between these characteristics and the development of degenerative spinal stenosis.

Clinical activity of brigatinib in ROS1-rearranged non-small cell lung cancer.

BACKGROUND: Brigatinib is a potent ROS1 inhibitor. The existing data on its clinical activity in ROS1-rearranged non-small cell lung cancer (NSCLC) are limited to four cases. METHODS: Six patients with ROS1-rearranged advanced NSCLC treated with brigatinib were identified through search of the internal databases of four participating cancer centers. Four additional patients were selected by PubMed and Google Scholar search. The objective response rate (ORR), progression-free survival (PFS) (RECIST v.1.1), duration of treatment (DOT), and safety were assessed. RESULTS: Of eight patients evaluable for response assessment (crizotinib naive-1, crizotinib resistant -7), three patients demonstrated a partial response (ORR-37%). One crizotinib-naive patient had an ongoing response at 21.6 months. Of seven crizotinib-resistant patients, two patients demonstrated a partial response (ORR-29%), and one patient (14%) had stable disease. PFS, available in four crizotinib-resistant patients, was 7.6 + , 2.9, 2.0, and 0.4 months. In crizotinib-resistant patients, DOT was 9.7 + , 7.7 + , 7.6 + , 4.0, 2.0, 1.1, 0.4 months, and was not reported in two patients. Genomic profiling in one responder revealed no ROS1 alteration, suggesting that the response was attributable to "off-target" brigatinib activity. In two patients with progressive disease, genomic profiling demonstrated a cMET exon 14 mutation + KRAS G12A mutation in one case, and a persisting ROS1-CD74 fusion + TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q mutations in the other. No grade 3-5 toxicity was observed. CONCLUSION: Brigatinib demonstrated modest activity in crizotinib-resistant ROS1-rearranged NSCLC. Its intracranial and systemic activity should be assessed in correlation with the underlying molecular mechanism of crizotinib resistance.

Our series is the first to describe brigatinib activity in ROS1-altered NSCLC. In crizotinib-resistant patients, ORR with brigatinib was 29%. PFS with brigatinib was 7.6+, 2.9, 2.0, and 0.4 months. DOT with brigatinib was 9.7+, 7.7+, 7.6+, 4.0, 2.0, 1.1, 0.4 months. The correlation between response and molecular resistance needs further exploration.

A retrospective six-year national survey of P. multocida infections in Israel.

Pasteurella multocida is the commonest organism infecting pet bites. Anecdotal reports tend to overemphasize dramatic outcomes. We aimed to study a large database of P. multocida infections. This retrospective survey of P. multocida infections in Israeli hospitals refers to the y 2000-2005. Clinical microbiologists were contacted by email and asked to perform a back-search of their hospital's records for isolates of P. multocida. The charts of patients growing P. multocida were abstracted into a structured questionnaire. 77 cases were identified in 12 hospitals, yielding an annual incidence of 0.19/100,000. The mean age was 49.2+/-26.5 y and the mortality rate was 2.6%. Those who died were >65 y of age, had diabetes mellitus or cirrhosis and were bacteraemic. One-third of the cases occurred in people aged > or =65 y. Cats caused most of these infections (54%). Surgery for debridement was common (53.7%), but no-one required amputation; a second- and third-look operation was necessary for these patients. Bacteraemia was found in 32.5% of patients and was significantly more common among those aged >60 y (p =0.044). Hospitalized patients with P. multocida have a favourable prognosis, apart from elderly and bacteraemic patients with comorbidities. Surgery and reoperations may be required in about half of the patients.

Mortality of patients with antibiotic-associated diarrhoea: the impact of Clostridium difficile.

Previous studies have shown conflicting results concerning mortality related to Clostridium difficile infection. The objective of this study was to determine the impact of C. difficile infection on short- and long-term mortality in hospitalised patients with antibiotic-associated diarrhoea. We therefore undertook a prospective case-control study of 217 hospitalised patients who received antibiotics, developed diarrhoea and underwent stool enzyme immunoassay for C. difficile TOX A/B. The Kaplan-Meier and the log-rank test were used to determine univariate survival analysis and a Cox regression model for multivariate analysis of 28 day and long-term mortality. Fifty-two (24%) of the 217 patients who met the study criteria were positive for C. difficile TOX A/B. The crude 28 day and long-term mortality rates of the entire cohort were 12.4% and 56%, respectively. On Cox regression analysis, hypoalbuminaemia, impaired functional capacity and elevated serum urea levels were found to be the only independent and statistically significant variables associated with long-term mortality. C. difficile toxin positivity per se was not associated with increased short- or long-term mortality rates. In conclusion, hypoalbuminaemia, renal failure, and impaired function capacity predict mortality due to antibiotic-associated diarrhoea, but C. difficile involvement by itself does not further increase the risk of death in these patients.

Pulmonary Mycobacterium simiae infection: comparison with pulmonary tuberculosis.

To identify the clinical and radiological features distinguishing Mycobacterium simiae respiratory infection from pulmonary tuberculosis, the demographics, underlying conditions, and clinical and radiological findings of 121 consecutive patients with pulmonary tuberculosis and 102 with M. simiae respiratory infection were compared retrospectively. In the M. simiae group, the patients were older (mean age 69 +/- 16 years vs. 47 +/- 21 years, p = 0.0001), with a female predominance (62% vs. 45%, p = 0.008). Only 4% were of Ethiopian origin compared to 25% of the tuberculosis group (p = 0.0001). M. simiae infection was associated with significantly higher rates of smoking history, underlying chronic obstructive pulmonary disease, zero human immunodeficiency virus (HIV) infection compared to 10% in the tuberculosis group (p = 0.001), blunted symptoms, and noncavitary infiltrates in the lower/middle lobes on chest X-ray. HIV-negative patients with M. simiae respiratory infection are distinguishable from patients with pulmonary tuberculosis by several demographic, clinical, and radiological features. These findings have important diagnostic and therapeutic implications.

Impact of 4% chlorhexidine whole-body washing on multidrug-resistant Acinetobacter baumannii skin colonisation among patients in a medical intensive care unit.

The prevalence of skin colonisation with Acinetobacter baumannii (ACBA) on admission to the medical intensive care unit (MICU) was studied in an institution endemic for ACBA bloodstream infections (BSIs). The impact of 4% chlorhexidine gluconate (4% CG) whole-body washing on the patients' ACBA skin colonisation was also determined. A prospective cohort trial in a MICU during March 2002 to December 2003 was performed, with a comparison between the prevalence and incidence of ACBA-BSIs obtained after intervention and retrospectively. During the intervention period, ACBA skin-screening swabs were taken from all patients on admission and periodically until discharge. Patients underwent whole-body disinfection with 4% CG immediately after obtaining the initial cultures. Disinfection was carried out on a daily basis until discharge, regardless of colonisation status. Of the 320 patients at ward admission, 55 (17%) yielded ACBA. The prevalence of ACBA colonisation among the remaining MICU patients was 5.5% at 24h and 1% at 48h following the disinfection regimen (P=0.002, OR: 2.4). Following a second screen, 80% of colonised patients were decolonised. Prevalence of ACBA-BSIs decreased from 4.6 to 0.6 per 100 patients (P < or = 0.001; OR: 7.6) and incidence decreased from 7.8 to 1.25 (85% reduction). We conclude that daily whole-body disinfection with 4% CG significantly reduced ACBA skin colonisation. This regimen may be considered in addition to well-known infection control measures, particularly in institutions with endemic rates of multidrug-resistant ACBA-BSIs.

Integration of computed tomographic coronary angiography into the invasive laboratory and into interventional coronary procedures.

Computed tomographic coronary angiography (CTA) has rapidly evolved to a level where it can be used not only for the diagnosis or exclusion of coronary artery disease, but also to a stage at which the value of CTA derived images in the catheterization laboratory during invasive procedures is under examination. This review will examine the possible role of CTA in selection of patients for invasive coronary angiography (ICA), in the planning of diagnostic ICA in patients who have undergone previous revascularization and the role of CTA in planning percutaneous interventional and surgical procedures.

Reduction of blood culture contamination rate by an educational intervention.

The efficacy of an educational intervention to prevent blood culture contamination (BCC) in internal medicine was studied in two medical wards in a busy tertiary-care hospital in which blood cultures were obtained by physicians rather than dedicated phlebotomists. Baseline BCC rates were 5.7% and 7.1% in intervention and control wards, respectively (p 0.6), compared with 1.95% and 6.7%, respectively, post-intervention (p < 0.001). Following multivariate analysis, only an absence of intervention was an independent variable associated with BCC. Thus simple educational intervention reduced BCC in internal medicine and was considered to be cost-effective.

Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease: effects of continuous positive air pressure treatment.

OBJECTIVES: To investigate the occurrence of nocturnal ischemic events in patients with obstructive sleep apnea syndrome (OSAS) and ischemic heart disease (IHD). BACKGROUND: Although previous reports documented nocturnal cardiac ischemic events among OSAS patients, the exact association between obstructive apneas and ischemia is not yet clear. It is also not known what differentiates between patients showing nocturnal ischemia and those that do not. METHODS: Fifty-one sleep apnea patients (age 61.3+/-8.3) with IHD participated in the study (after withdrawal of beta-adrenergic blocking agents and anti-anginotic treatment). All patients underwent whole-night polysomnography including ambulatory blood pressure recordings (30 min interval) and continuous Holter monitoring during sleep. A control group of 17 OSAS patients free from IHD were also similarly studied. Fifteen of the 51 patients were also recorded under continuous positive airway pressure (CPAP). RESULTS: Nocturnal ST segment depression occurred in 10 patients (a total of 15 events, 182 min), of whom six also had morning ischemia (06-08 am). Five additional patients had only morning ischemia. No ischemic events occurred in the control group. Age, sleep efficiency, oxygen desaturation, IHD severity and nocturnal-double product (DP) values were the main variables that significantly differentiated between patients who had ischemic events during sleep and those who did not. Nocturnal ischemia predominantly occurred during the rebreathing phase of the obstructive apneas, and it is characterized by increased heart rate (HR) and DP values. Treatment with continuous positive airway pressure significantly ameliorated the nocturnal ST depression time from 78 min to 33 min (p<0.001) as well as the maximal DP values (14,137+/-2,827 vs. 12,083+/-2,933, p<0.001). CONCLUSIONS: Exacerbation of ischemic events during sleep in OSAS may be explained by the combination of increased myocardial oxygen consumption as indicated by increased DP values and decreased oxygen supply due to oxygen desaturation with peak hemodynamic changes during the rebreathing phase of the obstructive apnea. Treatment with CPAP ameliorated the nocturnal ischemia.

Microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile neutropenic oncology patients: comparison between two consecutive time periods with use of different antibiotic treatment protocols.

This study was devised to look at trends in the microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile oncology patients. The retrospective study compared various microbiological aspects recorded for febrile oncology neutropenic patients treated with two different empirical antibiotic regimens (ceftazidime plus gentamicin during 1998-1999 and piperacillin/tazobactam plus amikacin during 2000-2002). Eighty-one bacteraemic episodes occurred in 41 patients. Overall, 132 (34 during 1998-1999 and 98 during 2000-2002) organisms were isolated: 84 (65%) Gram-negative bacteria, 39 (30%) Gram-positive bacteria and 7 (5%) fungi. Enterobacter spp. incidence decreased from 18 to 6% (P=0.07) while the recovery rates of Gram-positive organisms increased from 24 to 32% (P=0.4) during 2000-2002 compared with 1998-1999. MRSA were not isolated from any episode of bacteraemia. Five (18%) of the 28 Escherichia coli and Klebsiella spp. isolates were beta-lactamase producers (80% [4/5] isolated during 2000-2002). Twenty-seven of 28, 27/27, 23/28, 20/25 and 27/28 of these isolates were susceptible to imipenem, piperacillin/tazobactam, gentamicin, ceftazidime and ciprofloxacin, respectively. Thirty-two of 34 (94%) and 60/74 (81%) of the Gram-negative organisms isolated during 2000-2002 were susceptible to piperacillin/tazobactam and ceftazidime, respectively (P=0.076). No major differences in the microbial spectrum and antibiotic susceptibilities were recorded between the two consecutive study periods. An increase in the number of extended beta-lactamase producing E. coli and Klebsiella spp. occurred during 2000-2002. All beta-lactamase producing organisms were susceptible to piperacillin/tazobactam and initial empirical therapy with piperacillin/tazobactam was more appropriate than ceftazidime to cover most of the pathogens causing bacteraemia.

Impact of conversion from an open ward design paediatric intensive care unit environment to all isolated rooms environment on incidence of bloodstream infections and antibiotic resistance in Southern Israel (2000 to 2008).

We studied the epidemiology, microbiology, clinical aspects and outcome of bloodstream infections (BSI) in a tertiary paediatric intensive care unit. All BSI episodes were prospectively identified and analysed. The paediatric intensive care unit moved in 2006 from an open-plan unit to a new (all single room) unit. Three hundred and fifty-three BSI episodes occurred in 299 of 4162 patients. Overall, BSI incidence was 85 per 1000 hospitalised children. Fewer BSI episodes occurred during the last two years of the study (2007 to 2008), compared with 2000 to 2006 (70 of 1061 admissions, 6.5% versus 283 of 3101 admissions, 9.1%, respectively, P=0.01). There were 127 of 340 (37.4%) community-acquired and 213 of 340 (62.6%) nosocomial BSI episodes (31 of 1000 and 51 of 1000, respectively). Nosocomial BSI episodes decreased during 2007 to 2008 versus 2000 to 2006 (37.7% versus 55.8%, P=0.03). In 448 instances, pathogens were isolated, 231 (52%) Gram-positive and 188 (42%) Gram-negative. Coagulase-negative Staphylococci, S. pneumoniae and S. aureus (41.1%, 19.9% and 11.7%, respectively) were the most common Gram-positive and Enterobacteriaceae spp. the most frequent Gram-negative organisms (45.2%, of them Klebsiella spp. and E. coli 40% and 29.4%, respectively). A significant decrease was recorded during 2007 to 2008 in Enterobacteriaceae resistance to piperacillin, gentamicin and ciprofloxacin. Thirty of 299 (10%, 9 with S. pneumoniae-BSI) patients died. A significant decrease in BSI and nosocomial incidence and Enterobacteriaceae spp. antibiotic resistance was recorded following the conversion of the paediatric intensive care unit from an open ward to an all isolated rooms environment.

HLA class II analysis in Jewish Israeli narcoleptic patients.

HLA class II was investigated in eight Jewish narcoleptic patients, representing the total of such patients known in Israel at present, and in three patients suffering from sleep disturbances other than narcolepsy. All (11 out of 11) patients carried the serologic specificities DR2, DQ6 (DQ1). At the DNA level, all narcoleptics were found to be DRB1*1501, DQA1*0102, DQB1*0602 which indicates that the susceptibility gene may be located within the HLA class II region, DR, and/or DQ. As for the nonnarcoleptic patients with idiopathic hypersomnia, they carried different alleles of DR2 and DQ6, namely DRB1*1502, DQA1*0103, DQB1*0601. This study confirms that the incidence of narcolepsy in Israel is extremely low and that HLA class II genes or a gene(s) tightly linked to them are involved in the disease.