KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa.

BACKGROUND: Chronic Pseudomonas aeruginosa (Pa) airways infection, exuberant local inflammation, and progressive lung function loss are hallmarks of cystic fibrosis (CF). KB001-A is an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of Pa. This 16-week study evaluated KB001-A associated effect on time-to-need for antibiotics for worsening respiratory signs and symptoms, as well as safety, and treatment-associated changes in symptom scores, inflammatory markers, and spirometry. METHODS: This was a randomized, double-blind, placebo-controlled, repeat-dose study in CF subjects with Pa. Intravenous 10mg/kg KB001-A or placebo infusions were administered at baseline and weeks 2, 4, 8, and 16, with a 4-week follow-up. Sputum inflammatory markers were assessed in a sub-study. Time-to-need for antibiotics was compared between groups by Kaplan Meier analysis and Cox proportional hazards modeling adjusting for randomization strata. RESULTS: Of 182 subjects, 169 received at least one infusion of KB001-A (n=83) or placebo (n=86). KB001-A was generally safe and well-tolerated as compared to placebo, with no significant emergent adverse effects other than one serious adverse event of elevated hepatic enzymes of unclear etiology. Time to need for antibiotics did not differ between groups (HR: 1.00; 95% CI: 0.69, 1.45, p=0.995). A 3.2 increase in ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p=0.003). Mean changes from baseline in log10 sputum neutrophil elastase (NE) had a non-significant decrease (-0.27, 95% CI: -0.58,0.04, p=0.084) while IL-8 concentrations at week 16 were significantly lower (-0.27, 95% CI: -0.55,0.00, p=0.048) among KB001-A subjects (n=16) relative to placebo (n=13). CONCLUSIONS: KB001-A was safe and well-tolerated and associated with a modest FEV1 benefit and reduction in select sputum inflammatory markers (IL-8). KB001-A was not associated with an increased time to need for antibiotics. The lack of efficacy seen with KB001-A may be due, in part, to the low levels of the type III secretion proteins previously reported in sputum of CF patients chronically infected with Pa.

Longitudinal development of initial, chronic and mucoid Pseudomonas aeruginosa infection in young children with cystic fibrosis.

BACKGROUND: While the emergence of chronic and mucoid Pseudomonas aeruginosa (Pa) infection are both associated with poorer outcomes among CF patients, their relationship is poorly understood. We examined the longitudinal relationship of incident, chronic and mucoid Pa in a contemporary, young CF cohort in the current era of Pa eradication therapy. METHODS: This retrospective cohort was comprised of patients in the U.S. CF Foundation Patient Registry born 2006-2015, diagnosed before age 2, and with at least 3 respiratory cultures annually. Incidence and age-specific prevalence of Pa infection stages (initial and chronic [≥ 3Pa+cultures in prior year]) and of mucoid Pa were summarized. Transition times and the interaction between Pa stage and acquisition of mucoid Pa were examined via Cox models. RESULTS: Among the 5592 CF patients in the cohort followed to a mean age of 5.5years, 64% (n=3580) acquired Pa. Of those, 13% (n=455) developed chronic Pa and 17% (n=594) cultured mucoid Pa. Among those with mucoid Pa, 36% (211/594) had it on their first recorded Pa+culture, while mucoid Pa emerged at or after entering the chronic stage in 12% (73/594). Mucoidy was associated with significantly increased risk of transition to chronic Pa infection (HR=2.59, 95% CI 2.11, 3.19). CONCLUSIONS: Two-thirds of early-diagnosed young children with CF acquired Pa during a median 5.6years of follow up, among whom 13% developed chronic Pa and 17% acquired mucoid Pa. Contrary to our hypothesis, 87% of young children who developed mucoid Pa did so before becoming chronically infected.

Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis.

BACKGROUND: Given the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols. METHODS: Response parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored. RESULTS: The most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening. CONCLUSIONS: Results from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

The CAPS Study: incidence, management and outcomes of cardiac arrest in pregnancy in the UK: a prospective, descriptive study.

OBJECTIVE: To describe the incidence, risks, management and outcomes of cardiac arrest in pregnancy in the UK population, with specific focus on the use of perimortem caesarean section (PMCS). DESIGN: A prospective, descriptive study using the UK Obstetric Surveillance System (UKOSS). SETTING: All UK hospitals with maternity units. POPULATION: All women who received basic life support in pregnancy in the UK between 1 July 2011 and 30 June 2014 (n = 66). METHODS: Prospective case identification through UKOSS monthly mailing. MAIN OUTCOME MEASURES: Cardiac arrest in pregnancy, PMCS, maternal death. RESULTS: There were 66 cardiac arrests in pregnancy, resulting in an incidence of 2.78 per 100 000 maternities (1:36 000; 95% CI 2.2-3.6). In all, 28 women died (case fatality rate 42%); 16 women arrested solely as a consequence of obstetric anaesthesia, 12 of whom were obese. Basic and advanced life support were rapidly delivered. Those who died were more likely to have collapsed at home. Perimortem caesarean section was performed in 49 women, 11 in the emergency department. The time from collapse to PMCS was significantly shorter in women who survived (median interval 3 versus 12 minutes, P = 0.001). Forty-six of 58 babies were born alive; 32 babies to surviving mothers and 14 to women who died. CONCLUSION: Cardiac arrest is rare in the pregnant UK population, however, nearly a quarter of cases are precipitated by obstetric anaesthesia, suggesting an opportunity to reduce the incidence further. Maternal survival rates of 58% were achieved with timely resuscitation, including PMCS, delay in which was associated with maternal death. Inpatient arrests were associated with higher survival rates than arrests that occurred outside the hospital setting. TWEETABLE ABSTRACT: 25% of cardiac arrest in pregnancy is caused by anaesthesia. Rapid perimortem section improves survival.

Downstream flow event sampling of acid mine drainage from the historic Mt Morgan Mine.

Numerous scientific reports concur that the Dee River is heavily impacted by acid mine drainage from the historic gold and copper mine at Mt Morgan, Central Queensland. The water quality along the Dee River, for 18 km downstream of the mine she to is junction with Fletcher Creek, is characterised by low pH, typically 2.8 to 4.2. With respect to metal concentrations, the Dee River has been described as one of Australia's most polluted rivers. Measurements of pH along the Dee River clearly demonstrated the movement of a slug of acidic water down the river during each of the four flow events between November 2000 and February 2001. Laboratory analysis of water samples collected during November indicated Al, Cu and Zn concentrations orders of magnitude above ANZECC guidelines. Fish kills occurred with each flow event and killed an estimated total of 26,000 fish.

Gamete intra-Fallopian transfer or in-vitro fertilization after failed ovarian stimulation and intrauterine insemination in unexplained infertility?

A prospective randomized study was designed to compare gamete intra-Fallopian transfer (GIFT) and in-vitro fertilization (IVF) and embryo transfer in the treatment of couples who have failed to conceive after at least three cycles of ovarian stimulation and intrauterine insemination (IUI). A total of 69 couples with primary unexplained infertility of at least 2 years' duration plus at least three failed cycles of ovarian stimulation and IUI were randomly allocated to either GIFT or IVF/embryo transfer. The clinical pregnancy rate was 34% after GIFT treatment and 50% after IVF/embryo transfer. This difference was not statistically significant. The twin rate in the IVF/embryo transfer group was higher than in the GIFT group (53 versus 17%, P = 0.005). We conclude that patients with unexplained infertility and failed ovarian stimulation and IUI can still achieve encouraging pregnancy rates with IVF/embryo transfer or GIFT. Since IVF/embryo transfer is the least invasive of the two procedures and may yield diagnostic information, we would favour this therapy; however, the number of embryos transferred should be reduced to two to reduce the risk of twin pregnancy.

Epidemiology of Lyme disease in Olmsted County, MN, 1975-1990.

Lyme disease has been reported in Minnesota since 1980. Until now, it has not been regarded as endemic in Olmsted County. We reviewed the medical records of all 68 cases of Lyme disease diagnosed in residents of Olmsted County for 1980-1990. Only 17 of the 68 cases met Centers for Disease Control surveillance criteria for definite Lyme disease (13 men, 4 women). Of these 17 cases, 3 were likely acquired in Olmsted County. The age and sex adjusted incidence rate was 2.3/100,000 (95% CI 1.1-3.4). Although reporting of Lyme disease is mandatory in Minnesota, only 7 suspected or definite cases were actually reported to public health officials. Of these, 4 met the case definition. In this population Lyme disease was both over-diagnosed and underreported. This observation questions current data and could have important health policy implications if confirmed nationally.

Use of captopril as early therapy for renal scleroderma: a prospective study.

We conducted a prospective study of captopril therapy in patients with scleroderma and combined hypertension and renal insufficiency. In all seven patients studied during a 1-year period, control of blood pressure was achieved, and in six of the seven, renal function stabilized or improved. The total daily dosage of captopril ranged from 32 to 100 mg, divided into doses taken every 6 to 8 hours. Although one patient had a suspected captopril-induced rash for a short time, none of the other patients had any adverse side effects. Renal biopsies were performed in six patients; in three of them, specimens were obtained both at the beginning and at the end of the study. The initial biopsy specimens showed changes that were similar to those described in other reports. Findings on repeat biopsies were unchanged except for evidence of chronicity. In the six patients with controlled blood pressure and improved or stabilized renal function, the improvement was maintained for 1 1/2 to nearly 3 years on this drug therapy. Using specific measurements of skin compliance and vascular blood flow in the upper extremities, we could detect no evidence, however, of concomitant improvement in these other features of the disease. Although the blood pressure was controlled with captopril, one patient had progressive skin induration, one had progressive pulmonary insufficiency, and another had progressive renal failure.

Trial of platelet-inhibiting drug in scleroderma. Double-blind study with dipyridamole and aspirin.

In a randomized, double-blind, controlled study, 28 patients with early scleroderma received dipyridamole (225 mg/day) and aspirin (975 mg/day) or placebo for 1-2 years. No significant clinical or objective laboratory improvement was noted in either group. Platelet survival time, plasma renin activity, and coagulation tests were not predictive of disease course. Biomechanical and vascular tests of the hands correlated with clinical extent of skin induration and presence of finger ulcers, respectively.

Objective evaluation of hand function in scleroderma patients to assess effectiveness of physical therapy.

A system was developed to evaluate the hand function of patients with scleroderma objectively in terms of joint contracture, range of movement, dexterity, strength, and skin compliance. Twelve patients with progressive systemic sclerosis were evaluated using this technique to determine the effectiveness of classic physical therapy methods. A statistically significant improvement in hand function was found after a single physical therapy treatment. This conservative mode of treatment may contribute to improved hand function in patients with scleroderma.

Chrysiasis resulting from gold therapy in rheumatoid arthritis: identification of gold by x-ray microanalysis.

A patient with blue-gray discoloration of the skin of her face, neck, and hands is described. She was a patient with rheumatoid arthritis who had received a large total cumulative dose of gold. Light microscopy of skin biopsy tissue from the forehead revealed deposits of heavy metal in macrophages. On electron microscopy, the particles were found in the lysosomes of the cell. X-ray microanalysis confirmed the presence of gold. This condition, which is called chrysiasis, may be incorrectly diagnosed as cyanosis.

Digital skin capillary flow of xenon-133 in rheumatoid arthritis.

An atraumatic method for measuring digital capillary blood flow with(133)xenon is described here. It has the advantage of not requiring the handling of xenon in the gaseous phase, and is a comfortable procedure for the patient. A study of rheumatoid patients without overt vaculitis, and controls showed similar values, suggesting that despite digital deformities, the digital blood flow of the usual rheumatoid is adequate.