Timing of Worsening Renal Function in Patients Hospitalized for Heart Failure Exacerbation Who Were Being Treated With Intravenous Diuretic Therapy.

BACKGROUND: This retrospective observational study investigated the incidence of worsening renal function (WRF) in patients hospitalized for heart failure (HF) and treated with intravenous diuretics in Japan. METHODS AND RESULTS: Associations between WRF at any point and HF treatments, and the effects of WRF on outcomes were evaluated (Diagnosis Procedure Combination database). Of 1,788 patients analyzed (mean [±SD] age 80.5±10.2 years; 54.4% male), 641 (35.9%) had WRF during a course of hospitalization for worsening HF: 208 (32.4%) presented with WRF before admission (BA-WRF; estimated glomerular filtration rate decreased by ≥25% from baseline at least once between 30 days prior to admission and admission); 44 (6.9%) had WRF that persisted before and after admission (P-WRF); and 389 (60.7%) had WRF develop after admission (AA-WRF). Delayed initial diuretic administration, higher maximum doses of intravenous diuretics during hospitalization, and diuretic readministration during hospitalization were associated with a significantly higher incidence of AA-WRF. Patients with WRF at any time point were at higher risk of death during hospitalization compared with patients without WRF, with adjusted hazard ratios of 3.56 (95% confidence interval [CI] 2.23-5.69) for BA-WRF, 3.23 (95% CI 2.21-4.71) for AA-WRF, and 13.16 (95% CI 8.19-21.15) for P-WRF (all P<0.0001). CONCLUSIONS: Forty percent of WRF occurred before admission for acute HF; there was no difference in mortality between patients with BA-WRF and AA-WRF.

Time to intravenous diuretic administration in patients hospitalized with heart failure: An observational study.

AIMS: To help establish optimized treatment strategies for congestion in patients with acute heart failure, this study aimed to provide a detailed summary of real-world diuretic use in hospitalized patients with heart failure requiring urgent therapy in Japan. METHODS AND RESULTS: This observational study used a Japanese medical records database to extract data of patients admitted to hospital with a heart failure diagnosis and an intravenous diuretic prescription from the day before admission to 2 days after. Time from hospital visit to first dose, second dose, and maximum dose of intravenous diuretics were determined. Patients were grouped according to whether they received diuretic modification, defined as an intravenous diuretic dose increase or concomitant use of other diuretics. RESULTS: Overall, 1577 patients were included in the study (without diuretic modification, n = 1140 [72.3%]; with diuretic modification, n = 437 [27.7%]). The study population was 49.5% female (n = 780) and the mean age ± standard deviation was 80.1 ± 12.7 years. Intravenous diuretic treatment was received within 1 h of their hospital visit in 43.5% of patients (686/1577) and ≤2 h in 16.4% of patients (258/1577). Among 437 patients with an inadequate response following their first dose, 42.1% received an intravenous dose titration, 56.5% received combination diuretics, and 1.4% received both. Over half of the patients (59.0% [258/437]) with diuretic modification received it after the first 24 h of the hospital visit. The median time from hospital visit to first dose titration was similar to time to first combination diuretic use (18.6 h and 17.0 h, respectively). The mean ± standard deviation duration of intravenous diuretic use was significantly longer for patients with versus without diuretic modification (6.3 ± 5.2 vs. 3.7 ± 3.2 days), and a significantly greater proportion of patients (44.6% [195/437] vs. 35.0% [399/1140]) received repeated intravenous diuretic administration. Other characteristics/outcomes of intravenous diuretic use were similar with versus without diuretic modification, including in-hospital death (15.6% [68/437] vs. 13.9% [159/1140]) and mean ± standard deviation length of hospitalization (21.9 ± 14.7 days vs. 22.1 ± 21.2 days). CONCLUSIONS: In Japan, real-world patterns of intravenous diuretic administration for patients with heart failure remains far from the time-sensitive approach recommended in Japanese, European, and United States guidelines.

Real-World Intravenous Diuretic Use to Treat Congestion in Patients With Heart Failure　- An Observational Study Using a Research Database.

Background: Intravenous (IV) diuretics are key in the treatment of acute heart failure, but the time of administration can affect outcomes. Using a medical database, we assessed the real-world usage and clinical impact of IV diuretics after admission. Methods and Results: This observational study included hospitalized patients with heart failure who received IV diuretics. Relationships between IV diuretic use and clinical outcomes (duration of hospitalization, in-hospital mortality, readmission) were evaluated using analysis of variance or logistic regression. Overall, 9,653 patients (51.1% male) were assessed (mean age 80.9 years). Most (89.1%) patients had IV loop diuretic treatment initiated on Day 1 of hospitalization and 68.0% achieved the maximum dose on that day. The median duration of hospitalization was 17.0 days. In-hospital mortality was 9.2%; 13.7% of patients were readmitted within 3 months after discharge. There were prognostic relationships between IV diuretic usage and both duration of hospitalization and in-hospital mortality. On multivariable analysis, the time of maximum dose had the biggest impact on outcomes. Duration of hospitalization was prolonged and in-hospital mortality rates increased when the time of maximum dose was delayed. There was little correlation between IV diuretic use and readmission following discharge. Conclusions: Short-term outcomes (duration of hospitalization, in-hospital mortality) correlated with the time of maximum IV diuretic dose; thus, early initiation and subsequent modification of appropriate congestion treatment is critical for prognostic improvement.

Quantifying the Benefits of Digital Biomarkers and Technology-Based Study Endpoints in Clinical Trials: Project Moneyball.

Introduction: Digital biomarkers have significant potential to transform drug development, but only a few have contributed meaningfully to bring new treatments to market. There are uncertainties in how they will generate quantifiable benefits in clinical trial performance and ultimately to the chances of phase 3 success. Here we have proposed a statistical framework and ran a proof-of-concept model with hypothetical digital biomarkers and visualized them in a familiar manner to study power calculation. Methods: A Monte Carlo simulation for Parkinson's disease (PD) was performed using the Captario SUM® platform and illustrative study technology impact calculations were generated. We took inspiration from the EMA-qualified wearable-derived digital endpoint stride velocity 95th centile (SV95C) for Duchenne muscular dystrophy, and we imagined a similar measurement for PD would be available in the future. DaTscan enrichment and "SV95C-like" endpoint biomarkers were assumed on a hypothetical disease-modifying drug pivotal trial aiming for an 80% probability of achieving a study p value of less than 0.05. Results: Four scenarios with different combinations of technologies were illustrated. The model illustrated a way to quantify the magnitude of the contributions that enrichment and endpoint technologies could make to drug development studies. Discussion/Conclusion: Quantitative models could be valuable not only for the study sponsors but also as an interactive and collaborative engagement tool for technology players and multi-stakeholder consortia. Establishing values of digital biomarkers could also facilitate business cases and financial investments.

Mozart ear: diagnosis, treatment, and literature review.

Mozart ear is a congenital auricular deformity, which is mainly characterized by a bulging appearance of the anterosuperior portion of the auricle, a convexly protruded cavum conchae, and a slit-like narrowing of the orifice of the external auditory meatus. It is said to be uncommon, and because no one has yet fully described neither the disease nor the treatment, the concept of Mozart ear has not been unified. This report describes a case of a 13-year-old girl presented with an unusual congenital deformity which showed the features of Mozart ear. It is an extremely rare deformity that only about 4 clinical cases have been reported in medical literature thereby a treatment method has not been fully discussed. For surgical correction of our cases, we excised deformed conchal cartilage, turned it over, regrafted, and maintained a cosmetically positive result. We also reviewed and described the origin, current concept, and treatment method of Mozart ear.

Morphologic study of normal, ingrown, and pincer nails.

BACKGROUND: Pincer nail has been confused with ingrown nail for decades. OBJECTIVE: The objectives were to analyze the circumferential length of pincer nail and the relationship between nail deformity and the underlying distal phalangeal shape. METHODS: The circumferential length of 53 pincer nails was determined at successive 5-mm intervals of the nail plate. Sixty great toes, including normal (n=20), ingrown (n=20), and pincer nails (n=20), were assessed with respect to body height, body weight, body mass index, nail height, nail width index, and nail height index. Nail angle and height of osteophyte were measured. RESULTS: Despite the presence or absence of overcurvature, the circumferential length displayed nearly identical values across the proximal to distal range of the nail. In the pincer nail group, only the correlation between the width and height indices was statistically significant; 50%, 80%, and 100% of cases were confirmed based on osteophyte presence in normal, ingrown, and pincer nails. CONCLUSION: The findings suggest that the mechanical cause may be associated with the over curved nail, which is affected by nail bed contraction. Results may support the hypothesis that an osteophyte of the distal phalanx may not be a cause of, but rather a result of, an overcurving deformity.

Orbital wall reconstruction with bone grafts from the outer cortex of the mandible.

AIM: The purpose of the study was to assess the efficacy of bone grafting from the mandibular outer cortex for reconstructing the orbital walls. MATERIAL AND METHODS: Bone grafting was performed in 75 patients. The site the transplants were harvested from were: A: mental region, B: area posterior to the mental foramen, C: ramus region. In order to obtain the appropriate curvature for the orbital floor, proper selection of the donor area is required. The bony defect size was confirmed pre-operatively from 3D-CT data. Bone, characteristically 2-3 mm thick, was harvested from each area and grafted into the blow-out fractures. RESULTS: Out of the 75 patients 13 cases underwent reconstruction using mandibular outer cortex bone from area A, 8 from area B, and 54 from area C. The maximum size available for harvest from area C was 7 x 4 cm; material from this area could also be used for the repair of both medial and inferior orbital wall defects if necessary. CONCLUSION: Bone harvest from the mandible affords several advantages including (1) ease of harvest, (2) ease of trimming, (3) appropriate size and curvature, (4) absence of functional disability, (5) no secondary deformity, (6) no visible scars, (7) post-operative immobilization not necessary, (8) absence of post-operative difficulties with respect to breathing and walking and (9) major complications are rare.

Cilostazol prevents amyloid ß peptide(25-35)-induced memory impairment and oxidative stress in mice.

BACKGROUND AND PURPOSE: Cilostazol may be effective in dementia associated with a cerebral ischaemia. In this study, we examined whether it exerts beneficial effects on learning and/or memory impairment induced by Aß(25-35) in mice, and compared its effects with those of aspirin. EXPERIMENTAL APPROACH: Aß(25-35) (9 nmol) was administered to mice i.c.v. Learning and memory behaviour were evaluated by measuring spontaneous alternation in a Y-maze and a step-down type passive avoidance test, on the 5th and 8th days after injection respectively. Levels of lipid peroxidation (malondialdehyde) and cytokines in the frontal cortex and hippocampus were measured 2, 3, 5 and 7 days after the Aß(25-35) injection. The effects of repeated administration of cilostazol and aspirin (both at 30 and 100 mg·kg(-1), p.o.) on any changes induced by Aß(25-35) were evaluated. KEY RESULTS: Repeated administration of cilostazol significantly attenuated the impairment of spontaneous alternation and the shortened step-down latency induced by Aß(25-35) . Aspirin did not show any beneficial effect. A significant increase in the levels of malondialdehyde (MDA) and IL-1ß (only measured in hippocampus) was observed 2, 3 and 5 days after the Aß(25-35) injection in the frontal cortex and hippocampus. Repeated administration of cilostazol (100 mg·kg(-1)) completely prevented the increase in MDA levels but failed to antagonize the increase in the expression of IL-1ß induced by Aß(25-35). CONCLUSIONS AND IMPLICATIONS: These results suggest that the protective effect of cilostazol on Aß(25-35)-induced memory impairment may be related to oxidative stress in the frontal cortex and the hippocampus.

Preparation of ternary platinum(II) complexes with N-(omega-phenylalkyl)-1,2-ethanediamine and 2,2'-dipyridine and the effect of the methylene chain length of the N-(omega-phenylalkyl)-1,2-ethanediamine in the complexes on intermolecular interactions with various arylsulfonates.

A series of ternary complexes comprised of platinum(II), 2,2'-dipyridine, and N-(omega-phenylalkyl)-1,2-ethanediamine was prepared by varying the number (n) of methylene chain carbons between the phenyl group and one of the amino groups of 1,2-ethanediamine. NMR measurements indicated that intramolecular stacking occurred for n=1 and intermolecular stacking occurred for n=3 for several of the aryl sulfonates.

Dependence of hydrolysis of beta-lactams with a zinc(II)-beta-lactamase produced from Serratia marcescens (IMP-1) on pH and concentration of zinc(II) ion: dissociation of Zn(II) from IMP-1 in acidic medium.

The pH dependence for the hydrolysis of beta-lactam antibiotics by a metallo-beta-lactamase (IMP-1) produced from Serratia marcescens was investigated varying the concentration of Zn(II). The activity of IMP-1 for imipenem was decreased at pH less than pH 5.3 without external addition of Zn(II) ions but was recovered with addition of Zn(II). Varying the concentration of external Zn(II), the molar activity of the enzyme, k(obs), that was defined by the velocity of hydrolysis of imipenem/concentration of IMP-1 was expressed by k(obs)=v(init)/[E](T)=k(max)[Zn]/(K(d)+[Zn]) in which K(d) stands for the dissociation constant between Zn(II) and IMP-1. The dissociation constants, K(d), vary with pH; K(d)=840 x 10(-6) M at pH 4.3 and K(d)=0.19 x 10(-6) M at pH 6.0. The plot of -log K(d) against pH showed a straight line having a slope of 4.0 below pH 5.0, showing the existence of four functional groups which may be protonated upon dissociation of Zn(II) ion(s). The k(cat), K(m), and k(cat)/K(m) of hydrolysis of imipenem and cephalothin in the presence of sufficient concentration of Zn(NO(3))(2) for saturation of IMP-1 with Zn(II) showed similar dependency to each other on pH between pH 6.0 and 9.0.