Final results of the global and Asia cohorts of KAMILLA, a phase IIIB safety trial of trastuzumab emtansine in patients with HER2-positive advanced breast cancer.

BACKGROUND: KAMILLA is a single-arm safety study of trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC; NCT01702571). We report the final analysis of cohort 2 (Asia) within the context of published cohort 1 (Global) findings. METHODS: Patients had HER2-positive, locally advanced, or metastatic BC progressing after chemotherapy and anti-HER2 therapy or ≤6 months after adjuvant therapy. The primary objective was to further evaluate T-DM1 (3.6 mg/kg, administered intravenously every 3 weeks) safety/tolerability, including the following adverse events of primary interest (AEPIs): grade ≥3 AEPIs (hepatic events, allergic reactions, thrombocytopenia, hemorrhage events), all grade ≥3 treatment-related AEs, and all-grade pneumonitis. RESULTS: KAMILLA enrolled 2185 patients (cohort 1, n = 2003; cohort 2, n = 182) as of 31 July 2019. Of these, 2002 and 181 per cohort were treated and included in the safety population. Approximately 70% of patients had two or more previous treatment lines in the metastatic setting. Median T-DM1 exposure was 5.6 and 5.0 months per cohort; median follow-up was 20.6 and 15.1 months. The overall AEPI rate was higher in cohort 2 (93/181; 51.4%) versus cohort 1 (462/2002; 23.1%), mostly driven by a higher grade ≥3 thrombocytopenia rate in cohort 2. In cohort 2, grade ≥3 thrombocytopenia was not associated with grade ≥3 hemorrhagic events and most (128/138) fully resolved. Grade ≥3 treatment-related AEPI rates were 18.4% (cohort 1) and 48.6% (cohort 2), the latter mainly due to thrombocytopenia. Any-grade pneumonitis rates were 1.0% and 2.2%. No new safety signals were identified. Median (95% confidence interval) progression-free survival was 6.8 months (5.8-7.6 months) and 5.7 months (5.5-7.0 months) in cohorts 1 and 2, respectively; median overall survival was 27.2 months (25.5-28.7 months) and 29.5 months (21.1 months to non-estimable). In both cohorts, median progression-free survival and overall survival decreased with increasing prior therapy lines. CONCLUSIONS: Cohort 2 results aligned with previous findings in Asian patients, supporting the manageable safety profile and use of T-DM1 in advanced BC.

Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers.

BACKGROUND: The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies. PATIENTS AND METHODS: This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated. RESULTS: Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively. CONCLUSIONS: Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.

Circulating IGF-I levels in monitoring and predicting efficacy during long-term GH treatment of GH-deficient adults.

OBJECTIVE: To investigate the effects of long-term GH in GH-deficient adults, as predicted by IGF-I levels. METHODS: Patients received GH, 5 microg/kg per day for 1 Month and 10 microg/kg per day for another 12-30 Months. Changes in body composition, cardiac structure/function, serum lipids and quality of life were measured. RESULTS: There was a significant increase in lean body mass (LBM) (2.21 kg; P<0.0001) after 6 Months, which was sustained throughout treatment. A larger increase occurred in males than females (2.97 vs 1.19 kg; P<0.0001). Total fat mass was reduced (2.56 kg; P<0.0001 (3.26 kg males, 1.63 kg females)). Responsiveness to GH varied greatly, but LBM changes correlated with IGF-I changes (P<0.004). Furthermore, thinner patients experienced greater and progressive LBM increases. There was an increase in ejection fraction (3.85+/-9.95%; P=0.0002) after 6 Months, sustained to 18 Months. These cardiac effects were equal for males and females, and did not correlate with IGF-I levels. Serum low-density lipoprotein/high-density lipoprotein ratios decreased within 6 Months, and were sustained thereafter. Quality of life improved significantly after 6 Months, an effect that was sustained/enhanced as treatment continued. No major adverse events were identified. CONCLUSIONS: Improved body composition is both reflected by IGF-I changes and predicted inversely by baseline adiposity. Other effects of GH replacement on cardiac function, dyslipidaemia and quality of life, however, do not correlate with circulating IGF-I concentrations. Our findings validate the importance of sustained GH therapy, but caution on the interpretation of IGF-I levels in monitoring the long-term effects of GH treatment.

Gender-specific responses of lean body composition and non-gender-specific cardiac function improvement after GH replacement in GH-deficient adults.

GH deficiency (GHD) in adulthood is accompanied by physical and psychological impairments. One hundred fifteen patients (67 male, 48 female) with pronounced GHD were enrolled in a randomized, double-blind, placebo-controlled study with objectives that included effects on body composition, cardiac structure, and function and safety of replacement therapy with recombinant human GH (Saizen). Sixty patients (31 male, 29 female) received GH at a dose of 0.005-0.010 mg/kg.d, and 55 patients (36 male, 19 female) received placebo for 6 months. Assessment of body composition by dual-energy x-ray absorptiometry demonstrated a treatment difference in lean body mass increase of 2.1 kg (between-group comparison, P < 0.0001), which was significantly greater among males than females (P < 0.0001) [males: GH, +3.13 kg (2.42, 3.84); placebo, +0.11 kg (-0.60, 0.82); and females: GH, +0.64 kg (-0.15, 1.44); placebo: -0.90 kg (-2.20, 0.39)] [mean change 0-6 months (95% confidence limits)] and was associated with IGF-I changes. The decrease in fat mass of 2.8 kg (between-group comparison, P < 0.0001) noted by DEXA was also evident from bioelectric impedance and anthropometric measurements. Echocardiography showed comparable improvement in left ventricular systolic function after GH treatment in both genders. End-systolic volume decreased by 4.3 +/- 10.5 ml (from 35.8 +/- 17.6 ml; between-group comparison, P = 0.035) and ejection fraction increased by 5.1 +/- 10.0% (from 55.0 +/- 11.2%; between-group comparison, P = 0.048), approaching normalcy. Diastolic function did not change as assessed by isovolumic relaxation time, early diastolic flow, diastolic flow secondary to atrial contraction, or ratio of peak mitral early diastolic and atrial contraction velocity. GH treatment was well tolerated, with adverse events primarily related to effects on fluid balance. No apparent relationship between IGF-I levels and the occurrence or severity of adverse events was identified. In conclusion, GH replacement therapy in adults with GHD demonstrated beneficial effects on lean body mass composition that was more pronounced in males than females. In contrast, cardiac function improvement appears to benefit both genders equally.

A randomised controlled trial of high versus low long chain triglyceride whole protein feed in active Crohn's disease.

BACKGROUND: Polymeric feeds have shown variable efficacy in active Crohn's disease (CD) with remission rates from 36% to 82%. Meta-analyses of elemental, peptide, and whole protein feeds have shown a strong negative correlation between remission rate in CD and the long chain triglyceride (LCT) content of the feed. We performed a randomised controlled double blind trial in patients with active CD comparing two single whole protein feeds with LCT supplying 5% or 30% of the total energy. METHODS: Fifty four patients with active CD (Crohn's disease activity index (CDAI) >200, serum C reactive protein (CRP) 10 mg/l) were randomised to a high or low LCT feed for three weeks. The total amount of energy supplied by fat was identical in the two feeds. Remission was defined as a CDAI < or =150 and response as a fall in CDAI of > or =70 or a CRP <10 mg/l. RESULTS: Overall remission rate by intention to treat was 26% for the low LCT feed and 33% for the high LCT feed (p=0.38). Response was achieved in 33% with the low LCT and in 52% with the high LCT feed (p=0.27). CRP <10 mg/l was achieved in 30% in the low LCT and 33% in the high LCT group (p=0.99). Thirty nine per cent (21/54) of patients withdrew before three weeks because of inability to tolerate the diet. Excluding patients unable to tolerate the diet, remission rates were 46% for low LCT and 45% for high LCT (p=0.99). DISCUSSION: This trial has shown no difference in the effect of low and high LCT whole protein feeds in active CD. The previously reported correlation between LCT content of diet and response in active CD is unlikely to be due to LCT itself and may be due to some other component of high LCT feeds.

Side effects of influenza vaccination in healthy older people: a randomised single-blind placebo-controlled trial.

OBJECTIVES: To investigate the frequency of side effects following influenza vaccination in healthy participants aged 65-74 years. MATERIALS AND METHODS: A single-blind randomised placebo-controlled trial was performed in general practices in central Liverpool on 729 healthy individuals (341 females and 388 males) aged 65-74 (median age 68.9) years, of whom 552 received influenza vaccine and 177 received placebo. The main outcome measures were analysed from adverse reactions reported by the subjects on a postal questionnaire 3 days after vaccination. RESULTS: 724 (99.3%) questionnaires were returned. 62 (11.3%) participants who received influenza vaccination complained of local symptoms compared with 9 (5.1%) participants who received placebo (difference 6.2%; 95% CI 1.3 to 10.0%; p = 0.02). 192 (35.1%) individuals who received influenza vaccine complained of one or more systemic side effects compared with 75 (42.4%) who received placebo (difference -7.3%; 95% CI -15.6 to 0.9%; p = 0.10). CONCLUSION: Healthy people belonging to this age group can be reassured that, when compared with placebo, influenza vaccination causes few, if any, systemic side effects and only a low incidence of local side effects.

Oral signs and symptoms as predictors of salivary gland hypofunction in general dental practice.

OBJECTIVE: To evaluate the signs and symptoms of oral dryness as predictors of salivary gland hypofunction (SGH) in general dental practice. DESIGN AND SETTING: Prospective study recruiting adult patients attending five general dental practices in Merseyside in 1999. MATERIALS AND METHOD: Patients were screened for subjective symptoms of oral dysfunction and clinical signs of oral dryness. Patients with oral symptoms or signs of SGH were invited to undergo sialometry. Results were analysed using multiple logistic regression. RESULTS: 1103 patients were screened for signs and symptoms of oral dryness, 115 reported continuous xerostomia, of these 65 were also clinically (subjectively) assessed as having a dry oral mucosa. One hundred and one patients attended for sialometry and 73% of these had objective evidence of SGH. Neither the patients' complaints of oral dryness or the assessment of dryness of the oral mucosa were significant predictors of SGH. CONCLUSIONS: Symptoms of oral dysfunction and clinical signs of oral dryness were not significant predictors of SGH in dental practice.

Chronic disease patient education: lessons from meta-analyses.

Twelve meta-analyses were identified concerning education for people with chronic diseases where behaviour modification is a part of the treatment regime. By combining the results of these meta-analyses a second stage descriptive meta-analysis was conducted. The aim of the exercise was to explore the effects of patient education and implications for educational treatment. The results provided evidence of the gaps that exist in current research practice. These gaps include the need to utilise rigorous research designs to explore the quantitative effects of patient education, and the need to qualitatively explore the processes by which these effects have transpired. Where randomised controlled trials had been conducted the effects of patient education were usually small and were only known for 6 months of follow-up. In addition, the educational interventions tested were generally poorly described, and failed to adhere to theoretical models. The results of this review have highlighted the need for practitioners to use theoretically based teaching strategies which include behaviour change tactics that affect feelings and attitudes. In alignment with these conclusions, the review has provided guidelines for future research practice.

Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery.

OBJECTIVES: To determine whether continued methotrexate treatment increases the risk of postoperative infections or of surgical complications in patients with rheumatoid arthritis (RA) within one year of elective orthopaedic surgery. DESIGN: A prospective randomised study of postoperative infection or surgical complications occurring within one year of surgery in patients with RA who underwent elective orthopaedic surgery. SUBJECTS: 388 patients with RA who were to undergo elective orthopaedic surgery. Patients who were receiving methotrexate were randomly allocated to groups who either continued methotrexate (group A) or who discontinued methotrexate from two weeks before surgery until two weeks after surgery (group B). Their complication rates were compared with complications occurring in 228 patients with RA (group C) who were not receiving methotrexate and who also underwent elective orthopaedic surgery. MAIN OUTCOME MEASURES: Signs of postoperative infection were recorded, including rubor, discharge, systemic infection, and frequency of wound dehiscence as well as the incidence of any surgical complication requiring a secondary revision procedure that occurred within one year of surgery. The frequencies of flare up activity of RA at six weeks and six months after surgery were also recorded. A flare of rheumatoid disease was defined as an increase in joint pain in two or more joints notified by the patient as well as by an increase in articular index of at least 25% after surgery. RESULTS: Signs of infection or surgical complications occurred in two of 88 procedures in group A (2%), 11 of 72 procedures in group B (15%), and 24 of 228 (10.5%) procedures in group C. The surgical complication or infection frequency in group A was less than that in either group B (p<0.003) or group C (p=0.026). At six weeks after surgery there were no flares in group A, six flares in group B (8%), and six flares in group C (2.6%). Logistic regression analysis of the overall surgical complication rate in all the patients with RA studied showed that methotrexate, whether continued or discontinued before surgery, did not increase the early complication rate in the patients with RA who underwent elective orthopaedic surgery. Other drugs-penicillamine, indometacin, cyclosporin, hydroxychloroquine, chloroquine, and prednisolone-all did significantly increase the risk of infection or surgical complication after elective orthopaedic surgery. The risk of surgery was also increased in the presence of intercurrent chronic diseases-diabetes, hypertension, bronchiectasis, psoriasis, asthma, and ischaemic heart disease. CONCLUSION: Continuation of methotrexate treatment does not increase the risk of either infections or of surgical complications occurring in patients with RA within one year of elective orthopaedic surgery. Thus methotrexate treatment should not be stopped in patients whose disease is controlled by the drug before elective orthopaedic surgery.

Age and medication are significant risk factors for xerostomia in an English population, attending general dental practice.

OBJECTIVE: To study the prevalence of xerostomia in an English population, attending general dental practice and relate it to age, medication and gender. DESIGN STUDY: Cross-sectional. SETTING: Five General Dental Practices in Merseyside, North of England. SUBJECTS: 1,103 adult patients attending for routine dental care. INTERVENTION: Questionnaire administered by dentists. MAIN OUTCOME MEASURES: Age, gender, systemic medication, reported oral dryness. RESULTS: 1,103 patients (654 females) were recruited, of whom 427 (39%) were aged 60 years or older. 26% of patients reported taking medication. The overall prevalence of xerostomia was 12.7% (males--10.3%, females 14.4%). Age, medication and female gender were found to be significant risk factors for xerostomia, using logistic regression analysis. CONCLUSIONS: The prevalence of xerostomia (12.7%) in an English population was lower than reported in previous North American and Swedish studies. Medication was a significant risk factor for xerostomia and a better predictor of risk status, than either age or gender.

Childhood sexual abuse and affective symptoms in women: a general population study.

BACKGROUND: Child sexual abuse (CSA) is associated, after controlling for other adversities, with a range of non-psychotic disorders in adult life. There is a need to clarify whether CSA contributes to risk of disorder in the absence of such adversities, and given that associations may be accounted for by genetic mechanisms, whether they are seen where the perpetrator of CSA is not a biological relative, and where there has been only one incident. METHODS: A questionnaire-based study of a socio-economically representative sample of women age 25-36 (N = 862) was carried out. Parental care and control were assessed using the Parental Bonding Instrument, and CSA using a previously validated questionnaire. Current affective symptoms were assessed from the depression scale of the GHQ-28. RESULTS: Low maternal and paternal care were associated with risk of abuse by a biologically unrelated perpetrator before the age of 11, but not during early adolescence. Low maternal care and CSA each made independent contributions to the prediction of affective symptoms. CSA by a non-relative was strongly associated with GHQ depression, as was CSA by a non-relative that had occurred only once. CONCLUSIONS: Quality of parental care probably influences risk of CSA by unrelated abusers in younger children, while there may be a combination of genetic and parental influences on the risk of abuse by a relative. The strong association of affective symptoms in adult life with CSA by a non-relative suggests an environmental effect. Studies, utilizing genetic designs, of the role of childhood trauma in relation to adult affective symptoms are needed.

Graft distortion after endovascular repair of abdominal aortic aneurysm: association with sac morphology and mid-term complications.

PURPOSE: To investigate the incidence, significance, and mechanism of stent-graft distortion after endovascular repair (EVR) of abdominal aortic aneurysm. METHODS: EVR of abdominal aortic aneurysm was performed in 51 cases (49 modular, bifurcated; 2 tube). Thirty-two patients were followed for 6 or more months and had equivalent baseline and follow-up images which could be used to determine changes in graft configuration. Sac dimensions were measured using computed tomographic (CT) images and graft-related complications were recorded. RESULTS: Amongst 32 patients evaluated on follow-up, there was graft distortion in 24. Distorted grafts were significantly (p = 0.002) associated with sac diameter reduction (mean 5 mm) and sac length reduction (mean 8.1 mm). All graft-related complications occurred in the limbs of eight distorted grafts, with a mean reduction of sac length in this group of 7.8 mm on reformatted CT images. CONCLUSION: There was a highly significant association between graft distortion and limb complications, and reduced sac dimensions.

Localisation by in situ hybridisation of S100A4 (p9Ka) mRNA in primary human breast tumour specimens.

Rodent S100A4 (p9Ka) induces a metastatic phenotype in benign rat mammary tumour cells and cooperates with the neu oncogene to produce metastatic tumours in a transgenic mouse model system. Human S100A4 possesses similar metastasis-inducing properties. S100A4 mRNA is now sought in human breast tumour-derived cell lines and tumour specimens. S100A4 mRNA is present in some cell lines derived from malignant breast cancers, but is not detectable in cells derived from benign breast tumours. In human tumour specimens, using in situ hybridisation, the mRNA for S100A4 is localised to the epithelial cells of carcinoma specimens, and in some normal breast specimens, to a stromal region surrounding the epithelial ducts. In carcinoma specimens, S100A4 mRNA is also found in the stromal region surrounding islands of cancer cells. For both the epithelial and stromal components, S100A4 mRNA is present at a higher level in carcinomas relative to benign breast tumour specimens. In general, there is a concordance between the S100A4 mRNA signal from the epithelial and stromal elements of the same carcinoma specimens. Using Northern blotting techniques, these results have been extended to a panel of 137 benign and malignant breast tumour specimens. The results show that S100A4 mRNA occurs in the more-malignant, rather than in the more-benign tumour specimens.

Sensitivity and limitations of high throughput fluorescent microsatellite analysis for the detection of allelic imbalance: application in lung tumors.

We have used two hexaplex fluorescent microsatellite assays and analysis on an automatic sequencer to determine allelic imbalance in lung tumors. The markers used are located close to tumor-suppressor genes, DNA repair genes and regions frequently lost in lung cancer. We present a reference interval and quantify the reproducibility of the assays as assessed by multiple repeat reactions for normal DNAs. The cut-off value was calculated to 0.77 (23% reduction of one allele intensity) which, to the best of our knowledge, is currently the lowest reported cut-off. Using these parameters we analysed 85 lung carcinomas. Eighty-three samples (97.6%) showed allelic imbalance in at least one locus. It is of note that by using a selection of only 6 markers, imbalance was detected in 81 (95.2%) of the samples. Loci 9p21 and 9p23 exhibited the greatest imbalance (77% and 75% respectively). The fractional allele loss (FAL) for the 3p markers examined was greater in squamous cell carcinomas than adenocarcinomas (t-test, p=0.0001) while no such difference was observed for 9p. The degree of imbalance of different markers within the same sample was divergent, indicating heterogeneity of genomic status (losses, amplifications, aneuploidy) in these tumors. In conclusion, we have established a robust experimental platform with high throughput, sensitivity and specificity for the detection of allelic imbalance in lung tumors. Such assays may be useful for the detection of allelic imbalance in clinical samples to trace genetically abnormal cells and thus assist in the identification of individuals at a high risk for developing lung cancer.

Fractional allele loss indicates distinct genetic populations in the development of squamous cell carcinoma of the head and neck (SCCHN).

Loss of heterozygosity (LOH) had been widely used to assess genetic instability in tumours and a high LOH on chromosome arms 3p, 9p and 17p has been considered to be a common event in squamous cell carcinoma of the head and neck (SCCHN). We have investigated LOH in 52 SCCHN using a range of microsatellite markers. LOH was observed in 69% of individuals on 17p using seven markers, in 64% of individuals on 3p using 17 markers and in 61% of individuals on 9p using 11 markers. Fractional allele loss (FAL) has been calculated for each tumour (FAL is the number of chromosomal arms showing LOH divided by the number of informative chromosomal arms) and a median FAL value of 0.25 was obtained in the 52 SCCHN studied. The LOH data were examined on the basis of FAL scores: low FAL (LFAL), 0.00-0.19; medium FAL (MFAL), 0.20-0.32; high FAL (HFAL), 0.33-0.88. HFAL tumours demonstrated a significantly higher LOH on chromosome arms 3p, 9p and 17p, with 94% LOH on 3p, 94% on 9p and 100% on 17p compared with LFAL tumours. Six of the 16 patients in the LFAL group were found to have no LOH on 3p, 9p or 17p and of these four had LOH at other sites, on chromosomes 2p25-p24, 5q21-22, 7pter-p22, 8q13-q22.1, 11q23.3, 13q32, 17q, 18p11.21, 18q21.31 and 19q12-q13.1. These results indicate that LFAL patients form a subset of SCCHN tumours with distinct molecular initiating events which may represent a discrete genetic population.

Use of contrast-enhanced ultrasound in follow-up after endovascular aortic aneurysm repair.

PURPOSE: To investigate the use of contrast-enhanced ultrasound in the detection of endoleak after endovascular repair of abdominal aortic aneurysm. MATERIALS AND METHODS: Eighteen patients underwent follow-up on 20 occasions after endovascular aortic aneurysm repair by arterial-phase contrast-enhanced spiral computed tomography (CT). All patients had unenhanced color Doppler ultrasound and Levovist-enhanced ultrasound on the same day. The ultrasound examinations were reported in a manner that was blind to the CT results. CT was regarded as the gold standard for the purposes of the study. RESULTS: There were three endoleaks shown by CT. Unenhanced ultrasound detected only one endoleak (sensitivity, 33%). Levovist-enhanced ultrasound detected all three endoleaks (sensitivity, 100%). Levovist-enhanced ultrasound indicated an additional six endoleaks that were not confirmed by CT (specificity, 67%; positive predictive value, 33%). In one of these six cases, the aneurysm increased in size, which indicates a likelihood of endoleak. Two of the remaining false-positive results occurred in patients known to have a distal implantation leak at completion angiography. CONCLUSION: In this small group of patients, contrast-enhanced ultrasound appears to be a reliable screening test for endoleak. The false-positive results with enhanced ultrasound may be due to the failure of CT to detect slow flow collateral pathways. Although the number of patients in this study is small, enhanced ultrasound may be more reliable than CT in detecting endoleak.

Nitric oxide production in meningococcal disease is directly related to disease severity.

OBJECTIVES: Meningococcal disease is a homogeneous and well-characterized form of sepsis. Cardiovascular collapse is prominent in severe meningococcal disease. Nitric oxide overproduction may be a mediator of cardiovascular collapse. We relate the level of nitric oxide metabolites, nitrates and nitrites, to disease severity in meningococcal disease. DESIGN: Prospective, nonrandomized study. SETTING: Tertiary referral pediatric intensive care unit. PATIENTS: Children admitted with a clinical diagnosis of meningococcal disease. INTERVENTIONS: Blood was sampled from children with meningococcal disease. Disease severity was scored using the Glasgow meningococcal septicemia prognostic score and pediatric risk of mortality score. Plasma nitrates and nitrites were measured in stored plasma using the Greiss reaction after conversion of all the nitrate to nitrite. MEASUREMENTS AND MAIN RESULTS: Twenty-two children were studied. In 19, the final diagnosis was meningococcal disease. Of the 19 children with meningococcal disease, 7 had a Glasgow meningococcal septicemia prognostic score of <8 (mild) and 12 had a Glasgow meningococcal septicemia prognostic score > or = 8 (severe). Three children died, all of these being in the severely affected group. Higher levels of nitrates and nitrites were seen in the more severely affected children (median admission nitrates and nitrites, 27.5 vs. 59.7 nmol/mL; p = 0.063; median peak nitrates and nitrites, 49.9 vs. 114 nmol/mL; p = .01) or those with an increased predicted mortality using pediatric risk of mortality (Spearman's p 0.742; p = .0003). CONCLUSIONS: Higher levels of nitrates and nitrites are seen in sicker children with meningococcal disease.

Hospital admission after day-case gynaecological laparoscopy.

We have examined aspects of the anaesthetic technique that may influence the likelihood of unplanned overnight hospital admission after ambulatory gynaecological laparoscopy and have determined if any anaesthetically controllable factors were involved. The retrospective audit involved 300 patients. All patients attended the day-case unit at the Liverpool Women's Hospital between September 1996 and May 1997. One hundred ASA I-II patients who had unplanned overnight admissions during this time were evaluated. For every admitted patient, two similar patients who did not require admission were studied. Variables such as patient age and anaesthetic technique were evaluated by logistic regression. Our results indicated that postoperative emesis was the commonest cause for admission. Significant factors increasing the likelihood of unplanned admission included returning from the recovery unit after 15:00, use of a laryngeal mask airway and undergoing diagnostic laparoscopy. Significant factors reducing the likelihood of admission were the use of fentanyl and rectally administered diclofenac.

Health of the Nation Outcome Scales: a case study in general psychiatry.

BACKGROUND: Health of the Nation Outcome Scales (HoNOS) were incorporated in a data set recording the routine clinical activities of a mental health team in Liverpool. AIMS: To evaluate the use of HoNOS in general adult psychiatry. METHOD: All consecutive patients who came in contact with the mental health team were administered HoNOS by the consultant psychiatrist. A cohort (n = 204) of patients was identified over a period of 8 months. All patients (n = 156) who had a repeat HoNOS after an interval of 6 months were included in the study. RESULTS: There was an overall reduction in HoNOS scores after an interval of 6 months, more so among patients with psychotic and affective disorders. Patients scoring on other disorders showed no change on HoNOS. The measured change in clinical state based on the Clinical Global Impression scale was broadly consistent with HoNOS scores. CONCLUSIONS: It was feasible to administer HoNOS during routine assessments, but HoNOS data were of limited value in care-planning in day-to-day clinical practice. The widespread adoption of HoNOS for use in routine clinical practice would be premature.

Human sperm head morphometric distribution and its influence on human fertility.

OBJECTIVE: To study the distribution of live sperm head size in semen and sperm preparations as a predictor of fertility. DESIGN: Prospective blind clinical trial. SETTING: Academic tertiary referral center. PATIENT(S): One hundred fifty-five patients undergoing IVF treatment. Females with conditions negatively influencing fertilization were excluded. INTERVENTION(S): Morphometric analysis (head area, major axis, minor axis, and elongation ratio) of video images of sperm in semen and swim-up preparations used for IVF treatment was performed with a Hamilton-Thorne analyzer V 8.1 (Hamilton-Thorn Research, Beverly, MA). MAIN OUTCOME MEASURE(S): Oocyte fertilization. RESULT(S): Seventy-four percent of patients achieved fertilization. Fertilizers and nonfertilizers had different sperm head area distribution. The fertilizers had a significantly smaller interquartile range of sperm head area and of major axis in both semen and sperm preparation compared with the nonfertilizers. A subgroup of men who had fathered a child naturally had a more uniform sperm head area in semen with a significantly smaller median compared with those who failed to father a child naturally with their healthy female partner. We used multiple logistic regression applying forward stepwise selection of variables in building three predictive models of probability of fertilization. CONCLUSION(S): Successful IVF or history of fathering a child was associated with a more uniform sperm head area in semen and sperm preparation.