Integrated twin-screw wet granulation, continuous vibrational fluid drying and milling: A fully continuous powder to granule line.

Highly homogeneous low-dose (50 µg) tablets were produced incorporating perfectly free-flowing granules prepared by a fully integrated Continuous Manufacturing (CM) line. The adopted CM equipment consisted of a Twin-Screw Wet Granulator (TSWG), a Continuous Fluid Bed Dryer (CFBD) and a Continuous Sieving (CS) unit. Throughout the experiments a pre-blend of lactose-monohydrate and corn starch was gravimetrically dosed with 1 kg/h into the TSWG, where they were successfully granulated with the drug containing water-based PVPK30 solution. The wet mass was subsequently dried in the CFBD on a vibratory conveyor belt and finally sieved in the milling unit. Granule production efficiency was maximized by determining the minimal Liquid-to-Solid (L/S) ratio (0.11). Design of Experiments (DoE) were carried out in order to evaluate the influence of the drying process parameters of the CFBD on the Loss-on-Drying (LOD) results. The manufactured granules were compressed into tablets by an industrial tablet rotary press with excellent API homogeneity (RSD < 3%). Significant scale-up was realized with the CM line by increasing the throughput rate to 10 kg/h. The manufactured granules yielded very similar results to the previous small-scale granulation runs. API homogeneity was demonstrated (RSD < 2%) with Blend Uniformity Analysis (BUA). The efficiency of TSWG granulation was compared to High-Shear Granulation (HSG) with the same L/S ratio. The final results have demonstrated that both the liquid distribution and more importantly API homogeneity was better in case of the TSWG granulation (RSD 1.3% vs. 4.5%).

Wet etch methods for InAs nanowire patterning and self-aligned electrical contacts.

Advanced synthesis of semiconductor nanowires (NWs) enables their application in diverse fields, notably in chemical and electrical sensing, photovoltaics, or quantum electronic devices. In particular, indium arsenide (InAs) NWs are an ideal platform for quantum devices, e.g. they may host topological Majorana states. While the synthesis has been continously perfected, only a few techniques have been developed to tailor individual NWs after growth. Here we present three wet chemical etch methods for the post-growth morphological engineering of InAs NWs on the sub-100 nm scale. The first two methods allow the formation of self-aligned electrical contacts to etched NWs, while the third method results in conical shaped NW profiles ideal for creating smooth electrical potential gradients and shallow barriers. Low temperature experiments show that NWs with etched segments have stable transport characteristics and can serve as building blocks of quantum electronic devices. As an example we report the formation of a single electrically stable quantum dot between two etched NW segments.

Magnetic Field Tuning and Quantum Interference in a Cooper Pair Splitter.

Cooper pair splitting (CPS) is a process in which the electrons of the naturally occurring spin-singlet pairs in a superconductor are spatially separated using two quantum dots. Here, we investigate the evolution of the conductance correlations in an InAs CPS device in the presence of an external magnetic field. In our experiments the gate dependence of the signal that depends on both quantum dots continuously evolves from a slightly asymmetric Lorentzian to a strongly asymmetric Fano-type resonance with increasing field. These experiments can be understood in a simple three-site model, which shows that the nonlocal CPS leads to symmetric line shapes, while the local transport processes can exhibit an asymmetric shape due to quantum interference. These findings demonstrate that the electrons from a Cooper pair splitter can propagate coherently after their emission from the superconductor and how a magnetic field can be used to optimize the performance of a CPS device. In addition, the model calculations suggest that the estimate of the CPS efficiency in the experiments is a lower bound for the actual efficiency.

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat.

BACKGROUND AND PURPOSE: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. EXPERIMENTAL APPROACHES: Ca2+ -dependent active force production (Factive ), its Ca2+ sensitivity (pCa50 ), the kinetic characteristics of Ca2+ -regulated activation and relaxation, and Ca2+ -independent passive force (Fpassive ) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 µM). KEY RESULTS: In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50 : 0.11 or 0.34 at 0.1 or 1 µM respectively). The concentration-response relationship of the Ca2+ sensitization was bell-shaped, with maximal effects at 0.3-1 µM OM (EC50 : 0.08 ± 0.01 µM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 µM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. CONCLUSIONS AND IMPLICATIONS: OM acted as a Ca2+ -sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production.

Myeloperoxidase evokes substantial vasomotor responses in isolated skeletal muscle arterioles of the rat.

AIMS: Myeloperoxidase (MPO) catalyses the formation of a wide variety of oxidants, including hypochlorous acid (HOCl), and contributes to cardiovascular disease progression. We hypothesized that during its action MPO evokes substantial vasomotor responses. METHODS: Following exposure to MPO (1.92 mU mL(-1)) in the presence of increasing concentrations of hydrogen peroxide (H2O2), changes in arteriolar diameter of isolated gracilis skeletal muscle arterioles (SMAs) and coronary arterioles (CAs) and in the isometric force in basilar arteries (BAs) of the rat were monitored. RESULTS: Myeloperoxidase increased vascular tone to different degrees in CAs, SMAs and BAs. The mechanism of increased vasoconstriction was studied in detail in SMAs. MPO-evoked vasoconstrictions were prevented by the MPO inhibitor 4-aminobenzhydrazide (50 µM), by endothelium removal in the SMAs. Surprisingly, the HOCl scavenger L-methionine (100 µM), the thromboxane A2 (TXA2) antagonist SQ-29548 (1 µM) or the non-specific cyclooxygenase (COX) antagonist indomethacin (1 µM) converted the MPO-evoked vasoconstrictions to pronounced vasodilations in SMAs, not seen in the presence of H2O2. In contrast to noradrenaline-induced vasoconstrictions, the MPO-evoked vasoconstrictions were not accompanied by significant increases in arteriolar [Ca(2+)] levels in SMAs. CONCLUSION: These data showed that H2O2 -derived HOCl to be a potent vasoconstrictor upon MPO application. HOCl activated the COX pathway, causing the synthesis and release of a TXA2-like substance to increase the Ca(2+) sensitivity of the contractile apparatus in vascular smooth muscle cells and thereby to augment H2 O2 -evoked vasoconstrictions. Nevertheless, inhibition of the HOCl-COX-TXA2 pathway unmasked the effects of additional MPO-derived radicals with a marked vasodilatory potential in SMAs.

Finite-bias Cooper pair splitting.

In a device with a superconductor coupled to two parallel quantum dots (QDs) the electrical tunability of the QD levels can be used to exploit nonclassical current correlations due to the splitting of Cooper pairs. We experimentally investigate the effect of a finite potential difference across one quantum dot on the conductance through the other completely grounded QD in a Cooper pair splitter fabricated on an InAs nanowire. We demonstrate that the nonlocal electrical transport through the device can be tuned by electrical means and that the energy dependence of the effective density of states in the QDs is relevant for the rates of Cooper pair splitting (CPS) and elastic cotunneling. Such experimental tools are necessary to understand and develop CPS-based sources of entangled electrons in solid-state devices.

Hepatitis C in Austria 1993-2000: reporting bias distort HCV epidemiology in Austria.

From 1993 to 2000 in Austria, the notification system registered 2232 cases of hepatitis C whereas 10 607 hospital cases were reported in the hospital discharge register (HDR). These differences can be explained by under-reporting due to lax reporting behaviour and stigma associated with this disease. The distribution of HCV infection varied geographically. The notification data showed the highest incidence rates in Tyrol, while HDR data showed highest hospitalisation rates in Vienna and Lower Austria. This study highlights the urgent need for a clear case definition at the national level and an electronic reporting system.

Tuberculosis in Austria 1995-99: geographical distribution and trends.

A descriptive analysis of routine surveillance data on tuberculosis (TB) from 1995 to 1999 was performed in Austria. The federal states of Vienna and Upper Austria showed the highest yearly incidences for all five years. In general, however, a decrease of the yearly incidence was observed for all federal states except for Carinthia (where there was a small increase of 3.2 %). In the cities of Vienna, Linz, Wels, Salzburg, Klagenfurt and St-Pölten, as well as in the regions of Eastern Tyrol, Southern Carinthia, and Southern Burgenland, the incidence was above average (>19 cases/100,000 for each). The number of cases per year and per district reported by the statutory reporting system were clearly in excess of those reported by hospitals. The comparison of the two datasets, however, showed a highly significant regional correlation of age standardised morbidity rates at district level. The findings are prone to reporting bias and might not reflect the real TB situation. The responsible health authorities should therefore consider the results as a 'working hypothesis in order to review the reporting behaviour at district level.

Contingency valuation and preferences of health states associated with side effects of antipsychotic medications in schizophrenia.

The purpose of this study was to investigate the construct validity and the test-retest reliability of the willingness to pay (WTP) method for estimating health state preferences associated with side effects of antipsychotic medication. Ninety-six schizophrenia patients on antipsychotics were asked (1) how much they would be willing to pay to get rid of side effects with 100 percent probability, (2) a standard gamble (SG) question measuring utilities of patient's health state associated with side effects, and (3) their WTP to get rid of side effects based on the utility found with SG. Patients were divided into three groups based on severity of side effects. There was a significant difference between side effect severity groups for (1) the utility associated with side effects (Kruskal-Wallis [K-W] chi-square = 8.48, p = 0.014), and (2) their WTP to get rid of side effects with either 100 percent probability (K-W chi-square = 14.32,p = 0.001) or based on the utility associated with side effects (K-W chi-square = 5.96, p = 0.051). There was a significant correlation between utility and the WTP based on utility (Spearman r = -0.42, p = 0.003). Because of a wide variation in side effects at the 1-month interval, we were unable to assess the test-retest reliability of SG and WTP. Our results suggest that WTP has some construct validity in valuating and measuring preferences of health states associated with side effects of antipsychotics in schizophrenia.

The Academy of Psychosomatic Medicine practice guidelines for psychiatric consultation in the general medical setting. The Academy of Psychosomatic Medicine.

This practice guideline seeks to provide guidance to psychiatrists who regularly evaluate and manage patients with medical illnesses. The guideline is intended to delineate the knowledge base, professional expertise, and integrated clinical approach necessary to effectively manage this complex and diverse patient population. This guideline was drafted by a work group consisting of psychiatrists with clinical and research expertise in the field, who undertook a comprehensive review of the literature. The guideline was reviewed by the executive council of the Academy of Psychosomatic Medicine and revised prior to final approval. Some of the topics discussed include qualifications of C-L consultants, patient assessment, psychiatric interventions (e.g., psychotherapy, pharmacotherapy), medicolegal issues, and child and adolescent consultations.

A prospective study of the impact of psychiatric comorbidity on length of hospital stays of elderly medical-surgical inpatients.

To determine the difference in length of hospital stay for geriatric medical-surgical inpatients with or without psychiatric comorbidity, the authors prospectively interviewed 467 admissions by using the Structured Clinical Interview for DSM-III-R and the Mini-Mental State Exam. At admission, 208 (44.5%) inpatients had a current psychiatric comorbidity, 51 (10.9%) had an anxiety disorder, 88 (18.8%) had a depressive disorder, and 126 (27%) had cognitive impairment. The patients with cognitive impairment had a significantly prolonged hospital stay compared with those without cognitive impairment (14.6 vs. 10.6 days). No difference existed in length of stay for the patients with and without anxiety disorders (11.6 vs. 11.6 days) or depressive disorders (11.0 vs 11.8 days). In view of the limited resources available for screening elderly medical-surgical inpatients for psychiatric comorbidity, this study suggests the utility of identifying cognitive impairment and targeting it for interventions to reduce the clinical burden and to decrease hospital stays.

Prenatal genetic carrier testing using triple disease screening.

CONTEXT: Rapid progress in gene discovery has dramatically increased diagnostic capabilities for carrier screening and prenatal testing for genetic diseases. However, simultaneous prenatal carrier screening for prevalent genetic disease has not been evaluated, and patient acceptance and attitudes toward this testing strategy remain undefined. OBJECTIVE: To evaluate an educational, counseling, and carrier testing program for 3 genetic disorders: Tay-Sachs disease (TSD), type 1 Gaucher disease (GD), and cystic fibrosis (CF) that differ in detectability, severity, and availability of therapy. DESIGN: Potential participants received education and genetic counseling, gave informed consent, chose screening tests, and completed pre-education and posteducation questionnaires that assessed knowledge, attitudes toward genetic testing, and disease testing preferences. SETTING: Medical genetics referral center. PATIENTS: Volunteer sample of 2824 Ashkenazi Jewish individuals enrolled as couples who were referred for TSD testing. INTERVENTION: Genetic counseling, education, and if chosen, genetic testing for any or all 3 disorders. MAIN OUTCOME MEASURE: Acceptance of screening for each of the 3 disorders. Secondary outcomes include attitudes toward genetic testing and reproductive considerations. RESULTS: Of the 2824 individuals tested for TSD, 97% and 95% also chose testing for CF and GD, respectively. The frequency of detected carriers was 1:21 for TSD, 1 :25 for CF, and 1:18 for GD. Twenty-one carriercoupleswere identified, counseled, and all postconception couples opted for prenatal diagnosis. Pre-education and posteducation questionnaires revealed that patients initially knew little about the diseases, but acquired disease information and increased knowledge of genetic concepts. Education and genetic counseling increased understanding and retention of genetic concepts and disease-related information, and minimized test-related anxiety. Although individuals sought screening for all 3 diseases, reproductive attitudes and decisions varied directly with disease severity and treatability. CONCLUSIONS: These findings emphasize the importance of genetic counseling for prenatal carrier testing and may improve understanding, acceptance, and informed decision making for prenatal carrier screening for multiple genetic diseases.

Pediatric AIDS at Mount Sinai Medical Center 1988-89: a study of costs and social severity.

Pediatric AIDS is a continuing problem because of maternal transmission. Medical management is often complicated by the loss of one or both parents and adverse home environments. This study explores the cost of inpatient and clinic care of children admitted with AIDS in 1988 or 1989 at Mount Sinai Medical Center in New York City, and also examines the social severity of the cases. Blue Shield allowances were used to price clinic visits and tests, and prices in a drug trade publication were used to determine medication costs. Inpatient costs calculated per person-month at risk amounted to $48,000 per year. Costs per person-month of the clinic care averaged $461 (38% of which was for drugs), annualized to around $5,500. These costs are higher than those shown by previous studies. A few cases requiring intensive inpatient services accounted for a large percentage of costs. The social severity analysis, based on the family environment at first admission and later, revealed that households were often stressed by chronic illnesses, drug abuse, marital problems and poor residential quality. Given the circumstances in which pediatric AIDS develops, the activities of social workers to strengthen families are essential to facilitating compliance, maintaining health and minimizing use of the hospital.

Operationalizing a bedside pen entry notebook clinical database system in consultation-liaison psychiatry.

No current system of computerized data entry of clinical information in consultation-liaison (C-L) psychiatry has been well received or has demonstrated that it saves the consultant's time. The inability to achieve accurate, complete, systematic collection of discrete variables and data entry in the harried C-L setting is a major impediment to the advancement of the subspecialty and health services research. The hand-held Notebook computer with Windows PEN ENTRY MICROCARES capabilities has permitted one-time direct entry of data at the time of collection at the patient's bedside. Variable choice and selection enhances the completeness and accuracy of data collection. For example, ICD-9, Axis III diagnoses may be selected from a "look-up" which at the same time automatically assigns the appropriate code and diagnostic-related groups, (DRG) number. A patient narrative can be typed at the nurse's station, a chart note printed for the medical record, and the MICRO-CARES literature database perused with the printing of selected citations, abstracts, and in some cases experts' commentaries for the consultee. The consultant's documentation time is halved using the NOTEBOOK WINDOWS PEN ENTRY MICRO-CARES software, with the advantage of more accurate and complete data description than with the traditional handwritten consultation records. Consultees preferred typewritten in contrast to handwritten notes. The cost of the hardware (about $2000) is less than that of an optical scanner, and it permits report generation and archival searches at the nurses' station without returning to the C-L office for scanning. Radio frequency or ethernet download from the Notebook permits direct data transfer to th C-L office archive computer.

Composition and funding. Consultation-liaison psychiatry services.

All of the programs in the Academy of Psychosomatic Medicine directory of U.S. consultation-liaison (C-L) fellowship training (N = 49) responded to a questionnaire to document composition and funding of their staff. The mean annual budget was $324,664 (range $40,000-$550,000), with a mean of 2.4 full-time equivalents and 1.6 fellowship training positions. A significant patient cohort and C-L staff and fellows exist in these programs to launch important hypothesis-generation studies.

Spontaneous abortion in immunodeficient SCID mice.

PROBLEM: Immunodeficient SCID mice on the CB-17 have been used to test the role of "rejection" in a xenogeneic blastocyst transfer model of recurrent miscarriage, but interpretation of the data requires knowing syngeneic within-species matings have a high success rate and do not require immunotrophic factors expected only in immunocompetent non-T-cell deficient mice. METHOD: Resorption rates were studied in a SCID CB-17 barrier facility that provided the mice used to test the role of immunology in the resorption model. RESULTS: Spontaneous resorption in syngeneically mated immunodeficient SCID mice on the CB-17 background occurred at an unexpectedly high rate and could not be prevented by treatment with anti-asialo GM1 antibody or GM-CSF, both of which are effective in ameliorating abortion in DBA/2J-mated CBA/J mice. Immunocompetent CB-17 +/+ mice showed an even higher rate of loss. The latter was also not affected by treatment with antiasialo GM1 antibody or by GM-CSF and was not prevented by tetracycline (which is effective in the DBA/2-CBA/J system) or progesterone treatment. Mating experiments showed a scid/+ x scid@+ cross gave the highest rate of loss, and it appeared that the presence of +/(+)-type embryos in the uterus could be augmenting abortion with selective discrimination against scid/scid embryos. High abortion rates were associated both with appearance of a coagulase-negative Staphylococcus sp. in feces and with loss of one component of the SPF flora. Decidual tissue from mated CB-17 +/+ mice showed premature release of TNF-alpha in absence of TGF-beta 2-related suppressor activity, and vascular lesions (fibrinoid necrosis), varying in extent, were associated with both scid/scid x scid/scid and +/+ x +/+ pregnancies. TNF-alpha also appeared prematurely in pregnant scid/scid mice, but the levels were lower (and areas of necrosis smaller than in +/+ x +/+ pregnancies). Outcrossing onto a C57B1/6 background dramatically reduced the abortion rate, indicating an important genetic effect on susceptibility with heterogeneity protecting against abortion. CONCLUSIONS: SCID mice on the CB-17 background do not have a high rate of successful syngeneic pregnancies, and a TNF-alpha induced vasculopathy may be responsible. Abortion was not caused by immunodeficiency leading to loss of immunotrophism because immunocompetent non-SCID CB-17 mice had a higher rate of loss. Factors augmenting the abortion rate included the presence of embryos of the +/+ genotype in the uterus and treatment with anti-asialo GM1 antibody. Abortion rates were not reduced by treatments effective in the DBA/2-mated CBA/J mouse model but were reduced by re-establishing a new colony with defined flora (a temporary effect) and by outcrossing mice with a different (C57B1/6) background. Together, the data suggest an infectious trigger (identity uncertain) of the vasculopathy and an important genetic influence on susceptibility with heterozygosity and a SCID mouse mutation providing against abortion a degree of protection.

APM task force on psychosocial interventions in the general hospital inpatient setting. A review of cost-offset studies.

Several investigations of interventions with psychiatric and medical comorbidity (CM) in the medical inpatient setting have been reported. These studies include psychiatric liaison screening and interventions, psychosocial screening, and standard consultation. The studies had a variety of outcome variables: 1) altered psychiatric morbidity; 2) lag time to identification of CM; 3) lag time to referring to mental health disciplines; 4) cost offset; and 5) discharge placement. Methodological and design problems confound many of the results, in particular, the lack of random control procedures. However, similarity of findings of the frequency of CM in the inpatient setting and patient response to early detection and treatment should stimulate further research into the effects of psychiatric interventions in the acute inpatient medical setting.

Identification of alcoholism and depression in a geriatric medicine outpatient clinic.

OBJECTIVE: To examine the utility of brief screening instruments for alcoholism and depression in the frail elderly medical outpatient. DESIGN: Cross-sectional examination. SETTING: Coffey Geriatric Outpatient Clinic, The Mount Sinai School of Medicine, New York City. SUBJECTS: Convenience sample of 84 consenting male and female outpatients over 62 years of age. MEASUREMENTS: The Michigan Alcohol Screening Test (MAST), CAGE questionnaire, and the Geriatric Depression Scale (GDS). RESULTS: Four subjects (5%) scored positive for alcoholism on the MAST, all of whom had been previously identified by the geriatric clinic staff. In contrast, the CAGE only identified 1 (1.4%) alcoholic subject. Thirty-two percent of subjects scored positive for depression on the GDS, yet only one-third of these depressed patients had been previously identified by the geriatric team as depressed. Among the depressed outpatients, 19% were labeled anxious and received anxiolytics from the geriatric medical staff. CONCLUSIONS: Whereas brief alcohol screening instruments to detect alcoholism did not augment the geriatrician's clinical assessment, screening for depression with the GDS may be an important adjunct to the identification of depression in geriatric medical patients.