A phase 2, randomized, blinded, dose-finding, controlled clinical trial to evaluate the safety, tolerability, and immunogenicity of a 24-valent pneumococcal conjugate vaccine (VAX-24) in healthy adults 65 years and older.

Despite current polysaccharide and conjugate vaccine use, pneumococcal diseases remain prevalent in older adults. VAX-24 is a 24-valent pneumococcal conjugate vaccine (PCV) containing eCRM, a proprietary carrier protein with non-native amino acids (para-azidomethyl-L-phenylalanine) that undergo site-specific conjugation to pneumococcal polysaccharides that have been activated with a small-molecule linker (dibenzocyclooctyne). Site-specific conjugation utilizing click chemistry enables consistent exposure of T-cell epitopes, reduction in carrier protein to pneumococcal polysaccharide ratio, and enhances manufacturing process consistency to improve PCVs by increasing serotype coverage while minimizing carrier suppression. Healthy adults aged 65 or older were randomized in a 1:1:1:1 ratio to receive a single injection of VAX-24 at 1 of 3 dose levels (1.1, 2.2, or a mixed dose of 2.2 or 4.4 mcg) or Prevnar 20® (PCV20) in a phase 2, blinded study. Primary outcome measures were solicited local and systemic events within 7 days post-vaccination, unsolicited adverse events (AEs) within 1 month, and serious AEs, medically attended AEs, or new onset of chronic disease within 6 months of vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) were measured pre-vaccination and at 1 month post-vaccination. Of 207 participants enrolled, 200 completed the trial. Safety profiles were comparable across the three VAX-24 doses and PCV20. Robust OPA and IgG immune responses were seen for all 24 serotypes. On average, immune responses to VAX-24 2.2 mcg dose were similar or higher compared to PCV20. In adults ≥ 65 years, VAX-24 had a safety profile similar to PCV20 through six months post-vaccination and induced robust OPA and IgG responses to all 24 serotypes, supporting prior data showing that site-specific conjugation allows for increased serotype coverage with similar or higher immune response vs other PCVs. The outcome of this phase 2 study further supports use of VAX-24 2.2 mcg dose in phase 3 trials. Clinicaltrials.gov: NCT05297578.

The efficacy and safety of ezetimibe/simvastatin combination compared with intensified lipid-lowering treatment strategies in diabetic subjects with and without metabolic syndrome.

AIMS: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS). METHODS: This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed. RESULTS: In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar. CONCLUSION: These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort.

Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6-24 weeks.

Aims: The aim of this analysis was to assess the overall safety and tolerability profiles of various statins + ezetimibe vs. statin monotherapy and to explore tolerability in sub-populations grouped by age, race, and sex. Methods: Study-level data were combined from 27 double-blind, placebo-controlled or active-comparator trials that randomized adult hypercholesterolemic patients to statin or statin + ezetimibe for 6-24 weeks. In the full cohort, % patients with AEs within treatment groups (statin: N = 10,517; statin + ezetimibe: N = 11,714) was assessed by logistic regression with terms for first-/second-line therapy (first line = drug-naïve or rendered drug-naïve by washout at study entry; second line = ongoing statin at study entry or statin run-in), trial within first-/second-line therapy, and treatment. The same model was fitted for age (< 65, ≥ 65 years), sex, race (white, black, other) and first-/second-line subgroups with additional terms for subgroup and subgroup-by-treatment interaction. Results: In the full cohort, the only significant difference between treatments was consecutive AST or ALT elevations ≥ 3 × upper limit of normal (ULN) (statin: 0.35%, statin + ezetimibe: 0.56%; p = 0.017). Significantly more subjects reported ≥ 1 AE; drug-related, hepatitis-related and gastrointestinal-related AEs; and CK elevations ≥ 10 × ULN (all p ≤ 0.008) in first-line vs. second-line therapy studies with both treatments. AEs were generally similar between treatments in subgroups, and similar rates of AEs were reported within age and race subgroups; however, women reported generally higher AE rates. Conclusions: In conclusion, in second-line studies, ongoing statin treatment at study entry likely screened out participants for previous statin-related AEs and tolerability issues. These results describe the safety profiles of widely used lipid-lowering therapies and encourage their appropriate and judicious use in certain subpopulations.

Ezetimibe added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for coronary heart disease with diabetes mellitus, metabolic syndrome or neither.

AIM: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are both associated with increased risk for atherosclerotic coronary heart disease (CHD). Thus, it is useful to know the relative efficacy of lipid-altering drugs in these patient populations. METHODS: A double-blind, parallel group trial of adult patients with hypercholesterolaemia at high-CHD risk receiving atorvastatin 40 mg/day compared atorvastatin 40 mg plus ezetimibe 10 mg (ezetimibe) vs. doubling atorvastatin to 80 mg. This post hoc analysis reports lipid efficacy results in patients grouped by diagnosis of T2DM, MetS without T2DM or neither. Per cent change from baseline at week 6 was assessed for LDL-C, total cholesterol, HDL-C , non-HDL-C , Apo A-I, Apo B and triglycerides. Safety was monitored through clinical and laboratory adverse events (AEs). RESULTS: Compared with doubling atorvastatin, atorvastatin plus ezetimibe resulted in greater reductions in LDL-C, triglycerides, Apo B, non-HDL-C, total cholesterol and lipid ratios in the T2DM, MetS and neither groups. Treatment effects were of similar magnitude across patient groups with both treatments, except triglycerides, which were slightly greater in the T2DM and MetS groups vs. neither group. Changes in HDL-C , Apo A-I and high sensitivity C-reactive protein (hs-CRP) were comparable for both treatments in all three groups. Safety and tolerability profiles were generally similar between treatments and across patient groups, as were the incidence of liver and muscle AEs. CONCLUSIONS: Compared with doubling atorvastatin to 80 mg, addition of ezetimibe to atorvastatin 40 mg produced greater improvements in multiple lipid parameters in high-CHD risk patients with T2DM, MetS or neither, consistent with the significantly greater changes observed in the full study cohort (clinical trial # NCT00276484).

Attainment of Canadian and European guidelines' lipid targets with atorvastatin plus ezetimibe vs. doubling the dose of atorvastatin.

BACKGROUND: Canadian and European treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as a primary treatment target for hypercholesterolaemia. OBJECTIVES: This post hoc analysis compared ezetimibe 10 mg (ezetimibe) added to atorvastatin vs. doubling the atorvastatin dose on achievement of the 2009 Canadian Cardiovascular Society (CCS) and the 2007 Joint European Prevention Guidelines primary and optional secondary lipid targets and high-sensitivity C-reactive protein (hs-CRP) levels. METHODS: After stabilisation on atorvastatin, hypercholesterolaemic patients at moderately high risk (MHR) for coronary heart disease (CHD) not at LDL-C < 2.6 mmol/l were randomised to atorvastatin 20 mg vs. doubling their atorvastatin dose to 40 mg; and patients at high risk (HR) for CHD not at LDL-C < 1.8 mmol/l were randomised to atorvastatin 40 mg plus ezetimibe vs. doubling their atorvastatin dose to 80 mg for 6 weeks. RESULTS: When treated with atorvastatin plus ezetimibe, MHR and HR patients had greater attainment of LDL-C, most lipids and lipoproteins and/or hs-CRP targets compared with doubling their atorvastatin dose. More MHR and HR patients achieved dual targets of LDL-C and: Apolipoprotein (Apo) B, total cholesterol (total-C), total-C/high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, Apo B/Apo A-I or hs-CRP with ezetimibe + atorvastatin treatment compared with doubling their atorvastatin dose. CONCLUSIONS: These results demonstrated greater achievement of single/dual treatment targets as set by Canadian and European treatment guidelines with ezetimibe added to atorvastatin 20 mg or 40 mg compared with doubling the atorvastatin dose to 40 mg or 80 mg in MHR and HR patients, respectively.

Granulomatous infectious diseases associated with tumor necrosis factor antagonists.

The relationship between the use of tumor necrosis factor antagonists and onset of granulomatous infection was examined using data collected through the Adverse Event Reporting System of the US Food and Drug Administration for January 1998-September 2002. Granulomatous infections were reported at rates of approximately 239 per 100,000 patients who received infliximab and approximately 74 per 100,000 patients who received etanercept (P<.001). Tuberculosis was the most frequently reported disease, occurring in approximately 144 and approximately 35 per 100,000 infliximab-treated and etanercept-treated patients, respectively (P<.001). Candidiasis, coccidioidomycosis, histoplasmosis, listeriosis, nocardiosis, and infections due to nontuberculous mycobacteria were reported with significantly greater frequency among infliximab-treated patients. Seventy-two percent of these infection occurred < or =90 days after starting infliximab treatment, and 28% occurred after starting etanercept treatment (P<.001). These data indicate a risk of granulomatous infection that was 3.25-fold greater among patients who received infliximab than among those who received etanercept. The clustering of reports shortly after initiation of treatment with infliximab is consistent with reactivation of latent infection.

Noninvasive monitoring of renal blood flow characteristics during acute renal failure in man.

Duplex Doppler ultrasound (DDU) was used to study the blood flow characteristics of the renal interlobar artery in 20 subjects with acute renal failure (ARF), 14 subjects with transient impairment of renal function and 23 control subjects with normal function. Renovascular resistance was assessed by pulsatility index (PI) and change in flow velocity by change in mean frequency shift (delta f). The 99% confidence intervals for PI in the three groups were 3.32-5.46, 1.58-2.34 and 0.99-1.33 respectively. Values for delta f were 0.2-0.38, 0.5-0.62 and 0.7-1.02 kHz respectively. Ten ARF patients recovered function, 99% confidence intervals for PI just prior to recovery were 0.9-1.48 and for delta f 0.52-1.02 kHz. There was increased renovascular resistance and reduced intrarenal blood flow velocity at the onset of ARF. These changes persisted during ARF; recovery of function occurred after they returned to normal. Similar, but less marked, changes were found in patients with a transient impairment of function.

Microcomputer processing of film radiographs.

An inexpensive image processing system, assembled from commercially available components and driven by "in-house" software, was tested as a means of processing radiographs obtained in a radiology department. In this preliminary study, the main interest was to investigate, through subjective appraisal, the ability of the system to recover the image quality of poorly exposed radiographs. Subsidiary objectives were to obtain some information regarding the specification limits of the system and its components, as well as some quantitative estimate of its advantages for clinical diagnosis. The system was used to process a set of film radiographs of an anthropomorphic chest phantom, produced under conditions that were designed to provide a wide range of image qualities. Following this, four sets of randomly ordered processed and unprocessed images were formally assessed by a group of experienced observers. Consensus opinion from the group indicated that significant improvement could be obtained through simple image processing. Some radiographs regarded as unacceptable became, after processing, acceptable to viewers.

Doppler time velocity waveform studies of the uterine artery and uterus.

This study describes a reliable and reproducible method of obtaining Doppler frequency shift waveforms from the uterine artery based on observations in 26 non-pregnant women. The waveforms were detected easily but direct display of the vessel was inconsistent. The values of the pulsatility index calculated from the waveforms had a mean of 3.25 (SD 0.83). The standard error of the mean was 0.16 and based on this, the 95% reference range was 1.21 to 5.29. The stage of the menstrual cycle did not affect the pulsatility index nor was there any significant difference between subjects who were nulliparous and those who had had previous pregnancies. These results show that Doppler ultrasound can be applied to the non-pregnant uterus and the data presented may be used as a baseline for the study of uterine pathology.

Nociceptive neurons of the raccoon lateral thalamus.

1. Responses to noxious mechanical and thermal stimuli were examined in 48 thalamic neurons in barbiturate or chloralose-anesthetized raccoons, with special attention to neurons whose peripheral receptive fields (RFs) included glabrous skin of the forepaw. Recording loci were in the core of the ventrobasal complex (VB; n = 32), its ventral or dorsal border (n = 5), or the medial division of the posterior nuclear group (POm; n = 11). 2. Twenty-one VB neurons and 7 POm neurons were classed as wide dynamic range (WDR), whereas 2 VB neurons and 4 POm neurons were classed as nociceptive specific (NS). Response properties of 14 light touch (LT) neurons located in VB were also examined. 3. WDR and NS neurons were not segregated, but rather were intermixed along the ventral and dorsal borders of VB, as well as in POm, and WDR and LT neurons were intermixed in the core of VB. Within the VB core, both LT and WDR neurons were somatotopically organized. 4. All WDR neurons had larger high-threshold than low-threshold RFs, and this difference was greater for POm neurons than for VB neurons. RF areas of LT neurons and low-threshold RF areas of WDR neurons were comparable to those previously reported for raccoon VB units. 5. Out of 25 WDR cells tested, 20 had heat thresholds > 53 degrees C; the range of thresholds in the remaining 5 was 49-53 degrees C. Four out of five NS neurons tested had heat thresholds > 53 degrees C; the threshold of the fifth was 51 degrees C. Of the six neurons with heat thresholds < or = 53 degrees C, two each were in the core of VB, along the border of VB, and in POm. 6. Sensitization to heat after a mild heat injury to the glabrous RF (53 degrees C for 90 s, or 55 degrees C for 30 s) occurred in 8 out of 16 neurons tested, and persisted for up to 2 h. Median thresholds decreased from > 53 degrees C before injury to 47 degrees C after injury, and responses to suprathreshold stimuli were enhanced. There was a significantly greater likelihood (P = 0.02) for sensitization to occur in POm neurons (6/7) than in VB neurons (2/9). 7. It is suggested that a small proportion of neurons located in VB and POm contribute to the sensation of heat pain. Furthermore, sensitization of these neurons may contribute to heat hyperalgesia after an injury to glabrous skin.

Practical use of duplex Doppler analysis of the renal vasculature in critically ill patients.

Duplex doppler examination of blood flow in renal interlobar arteries was analysed in twelve critically ill patients before and during low-dose dopamine infusion (2 micrograms/kg/min). Renal vasodilatation and increased blood flow were observed with dopamine, confirming results with indirect or invasive techniques. The doppler ultrasound technique is entirely non-invasive, is simple and quick to carry out, provides instant results, and will allow tailoring of inotropic support in critically ill patients to provide optimum renal blood flow.

An assessment of the relationship between vasoconstrictor assay findings, clinical efficacy and skin thinning effects of a variety of undiluted and diluted corticosteroid preparations.

We have evaluated a number of diluted and undiluted topical corticosteroid preparations in terms of vasoconstrictor potency, clinical efficacy and skin thinning effects. We conclude that, for the materials tested so far, an area under the curve measurement obtained from serial readings of the vasoconstrictor assay allows reasonably accurate predictions to be made concerning the relative clinical efficacy and skin thinning potential of these agents. If further work with a wide range of topical corticosteroids confirms our findings, the value of the vasoconstrictor assay as a predictive model will be enhanced.

Preliminary Doppler studies on the uterine artery and myometrium in trophoblastic tumours requiring chemotherapy.

The uterine circulation in 38 patients with invasive mole or choriocarcinoma were investigated using Doppler ultrasound. Twenty-six non-pregnant and 23 pregnant volunteers were assessed in a similar fashion to act as control groups. The pulsatility indices were significantly lower in the patients with trophoblastic disease when compared with the non-pregnant and pregnant groups (Student's t-test; P less than 0.001 and P less than 0.02 respectively). The uterine circulation in persistent trophoblastic diseases shows a characteristic Doppler profile suggesting the presence of large low resistance blood vessels. This may be useful in the initial assessment of these tumours before cytotoxic chemotherapy.

Interpretation of duplex Doppler ultrasound in renal transplants in the early postoperative period.

A prospective study of duplex Doppler ultrasound in 29 renal transplants was undertaken to determine how to interpret Doppler findings in the immediate postoperative period. The study included intraoperative pulsed Doppler recordings from grafts immediately following release of vessel clamps. Subsequent follow-up studies were performed in the immediate postoperative period. Intraoperative Doppler appearances in the group as a whole were normal; there was a significant deterioration in Doppler appearances in the first 24-48 h of the postoperative period. In the absence of rejection subsequent Doppler appearances returned to normal. An abnormal Doppler appearance immediately following transplantation should be an expected result. If the Doppler fails to improve, or deteriorates having started to improve, rejection should be strongly suspected.