Designing schedule configuration of a hybrid appointment system for a two-stage outpatient clinic with multiple servers.

Even though several clinics serve patients in more than one stage (e.g., visit nurse and then visit doctor) and employ multiple providers in each stage, most of the previous work on appointment system design considers a simplified single-stage single-server clinic. Motivated by a real-life clinic setting, this paper aims to determine the schedule configuration of a hybrid appointment system (i.e., the number of pre-booking and same-day time slots reserved for a physician along with their positions in the schedule) for a two-stage multi-server clinic. A stochastic optimization model is developed to obtain a schedule configuration that minimizes the expected total cost - a weighted sum of excessive patient waiting time, resource idle time, resource overtime, and denied appointment requests. Owing to its computational complexity, we estimate the expected total cost using the sample average approximation method. The proposed model is verified and validated using small test instances and subject matter experts. A case study of a family medicine clinic in Pennsylvania is used to illustrate the proposed approach. The schedule generated by the proposed model results in a significantly lower expected cost compared to the approximated single-stage system's best schedule configuration and clinic's existing configuration. Further, sensitivity analysis is conducted to assess the impacts of no-show rate, service time variation, and cost ratios on the schedule configuration. Our findings demonstrate that the schedule configuration is sensitive to changes in the average no-show rate and cost ratios but is not significantly impacted by service time variation. Several managerial insights are also drawn from our analysis. Finally, we provide directions for future research that also highlights the potential to use the revenue management approach to address the problem under study.

Perceived functional impairment and spirituality/religiosity as predictors of depression in a Sri Lankan spinal cord injury patient population.

STUDY DESIGN: Cross-sectional, questionnaire-based study. OBJECTIVES: To test the hypothesis that self-perceived functional impairment and religiosity/spirituality (S/R) predict depression among traumatic spinal cord injury (SCI) patients in Sri Lanka. SETTING: Ragama Rheumatology and Rehabilitation Hospital, Ragama, Sri Lanka. METHODS: The Spinal Cord Independence Measure, Benefit Through Spirituality/Religiosity Scale, Sheehan Disability Inventory and Beck Depression Inventory-II (BDI-II) were administered to 61 consenting in-patients with traumatic SCI between June and July 2014. A linear regression model on BDI-II score was developed to examine the impact of self-perceived functional impairment and S/R activities on psychiatric outcomes in context of various sociodemographic variables. RESULTS: Psychiatric consequences of SCI were reflected in a 41% prevalence of depression. Thirty-six percent (R2=0.36) of the variance in BDI-II scores (F(5, 55)=6.07, P<0.001) was explained by the regression model. Functional impairment (ß=0.54, t(55)=4.73, P<0.001) and perceived benefit through S/R activities (ß=-0.31, t(55)=-2.55, P<0.05) emerged as the strongest predictors for depression severity. CONCLUSIONS: Perceived functional impairment in work, social and family domains predicted depressive symptomatology among SCI inpatients in Sri Lanka, while perceived benefit through S/R protected against depression. The findings emphasize the need for rehabilitative programming to support patients' S/R activities and mental wellbeing, promoting reintegration into their community roles.

Prediction of m6A and m5C at single-molecule resolution reveals a transcriptome-wide co-occurrence of RNA modifications.

The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytosine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI's capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.

Association of ethnicity with antipsychotic dosage using STRUCTURE analysis.

Several studies have examined whether ethnicity as an independent factor can influence the individual's dosage of antipsychotics. However, there has been inconsistency in the results of these studies, particularly between white and non-white populations. This retrospective study tests the hypothesis of different dosing of antipsychotics in white Europeans vs. non-white Europeans considering both the self-reported ethnicity and the geographical ancestry calculated using 196 DNA markers.We collected self-reported ethnicity and DNA samples from 209 schizophrenia patients. We tested the association between self-reported and genetically-determined ethnicity with the chlorpromazine equivalent dose of each antipsychotic prescribed at the time of the assessment.We did not find any significant difference between self-reported white European -ethnicity and chlorpromazine equivalent doses (p=0.972). Furthermore, when we considered the geographical ancestry determined by the 196 SNPs, we could not find any correlation between the European ancestry and chlorpromazine equivalent dose.Our preliminary analysis shows that there is no evidence that different ethnic groups receive different dose of antipsychotics.

Universal pre-mixing dry-film stickers capable of retrofitting existing microfluidics.

Integrating microfluidic mixers into lab-on-a-chip devices remains challenging yet important for numerous applications including dilutions, extractions, addition of reagents or drugs, and particle synthesis. High-efficiency mixers utilize large or intricate geometries that are difficult to manufacture and co-implement with lab-on-a-chip processes, leading to cumbersome two-chip solutions. We present a universal dry-film microfluidic mixing sticker that can retrofit pre-existing microfluidics and maintain high mixing performance over a range of Reynolds numbers and input mixing ratios. To attach our pre-mixing sticker module, remove the backing material and press the sticker onto an existing microfluidic/substrate. Our innovation centers around the multilayer use of laser-cut commercially available silicone-adhesive-coated polymer sheets as microfluidic layers to create geometrically complex, easy to assemble designs that can be adhered to a variety of surfaces, namely, existing microfluidic devices. Our approach enabled us to assemble the traditional yet difficult to manufacture "F-mixer" in minutes and conceptually extend this design to create a novel space-saving spiral F-mixer. Computational fluid dynamic simulations and experimental results confirmed that both designs maintained high performance for 0.1 < Re < 10 and disparate input mixing ratios of 1:10. We tested the integration of our system by using the pre-mixer to fluorescently tag proteins encapsulated in an existing microfluidic. When integrated with another microfluidic, our pre-mixing sticker successfully combined primary and secondary antibodies to fluorescently tag micropatterned proteins with high spatial uniformity, unlike a traditional pre-mixing "T-mixer" sticker. Given the ease of this technology, we anticipate numerous applications for point-of-care devices, microphysiological-systems-on-a-chip, and microfluidic-based biomedical research.

A comparative study on effective cell disruption methods for lipid extraction from microalgae.

AIMS: To compare effective cell disruption methods for lipid extraction from fresh water microalgae. METHODS AND RESULTS: Chlorella sp., Nostoc sp. and Tolypothrix sp. were isolated from fresh water ponds in and around Gandhigram, Dindigul District, Tamilnadu, India, and used for lipid extraction. Different methods, including autoclaving, bead beating, microwave, sonication and a 10% NaCl solution treatments, were tested to identify the most effective cell disruption method. The total lipids from three microalgal species were extracted using a mixture of chloroform and methanol. Fatty acid composition was detected by gas chromatography (GC). Nostoc sp. and Tolypothrix sp. showed higher oleic acid content of 13.27 mg g(-1) dw and 17.75 mg g(-1) dw, respectively, whereas Chlorella sp. had high linoleic acid content of 17.61 mg g(-1) dw when the cells were disrupted using the sonication method. CONCLUSIONS: Finally, the sonication method was found to be the most applicable and efficient method of lipid extraction from microalgae. The highest lipid content was extracted from Chlorella sp. SIGNIFICANCE AND IMPACT OF THE STUDY: In biodiesel production from microalgae, lipid extraction is a crucial step and important as cell disruption comes in this step. Therefore, the appropriate cell disruption method and device is a key to increase the lipid extraction efficiency.

Zn2(+)-induced subconductance events in cardiac Na+ channels prolonged by batrachotoxin. Current-voltage behavior and single-channel kinetics.

The mechanism of voltage-dependent substate production by external Zn2+ in batrachotoxin-modified Na+ channels from canine heart was investigated by analysis of the current-voltage behavior and single-channel kinetics of substate events. At the single-channel level the addition of external Zn2+ results in an increasing frequency of substate events with a mean duration of approximately 15-25 ms for the substate dwell time observed in the range of -70 to +70 mV. Under conditions of symmetrical 0.2 M NaCl, the open state of cardiac Na+ channels displays ohmic current-voltage behavior in the range of -90 to +100 mV, with a slope conductance of 21 pS. In contrast, the Zn2(+)-induced substate exhibits significant outward rectification with a slope conductance of 3.1 pS in the range of -100 to -50 mV and 5.1 pS in the range of +50 to +100 mV. Analysis of dwell-time histograms of substate events as a function of Zn2+ concentration and voltage led to the consideration of two types of models that may explain this behavior. Using a simple one-site blocking model, the apparent association rate for Zn2+ binding is more strongly voltage dependent (decreasing e-fold per +60 mV) than the Zn2+ dissociation rate (increasing e-fold per +420 mV). However, this simple blocking model cannot account for the dependence of the apparent dissociation rate on Zn2+ concentration. To explain this result, a four-state kinetic scheme involving a Zn2(+)-induced conformational change from a high conductance conformation to a substate conformation is proposed. This model, similar to one introduced by Pietrobon et al. (1989. J. Gen. Physiol. 94:1-24) for H(+)-induced substate behavior in L-type Ca2+ channels, is able to simulate the kinetic and equilibrium behavior of the primary Zn2(+)-induced substate process in heart Na+ channels. This model implies that binding of Zn2+ greatly enhances conversion of the open, ohmic channel to a low conductance conformation with an asymmetric energy profile for Na+ permeation.

Divalent cation selectivity for external block of voltage-dependent Na+ channels prolonged by batrachotoxin. Zn2+ induces discrete substates in cardiac Na+ channels.

The mechanism of block of voltage-dependent Na+ channels by extracellular divalent cations was investigated in a quantitative comparison of two distinct Na+ channel subtypes incorporated into planar bilayers in the presence of batrachotoxin. External Ca2+ and other divalent cations induced a fast voltage-dependent block observed as a reduction in unitary current for tetrodotoxin-sensitive Na+ channels of rat skeletal muscle and tetrodotoxin-insensitive Na+ channels of canine heart ventricular muscle. Using a simple model of voltage-dependent binding to a single site, these two distinct Na+ channel subtypes exhibited virtually the same affinity and voltage dependence for fast block by Ca2+ and a number of other divalent cations. This group of divalent cations exhibited an affinity sequence of Co congruent to Ni greater than Mn greater than Ca greater than Mg greater than Sr greater than Ba, following an inverse correlation between binding affinity and ionic radius. The voltage dependence of fast Ca2+ block was essentially independent of CaCl2 concentration; however, at constant voltage the Ca2+ concentration dependence of fast block deviated from a Langmuir isotherm in the manner expected for an effect of negative surface charge. Titration curves for fast Ca2+ block were fit to a simplified model based on a single Ca2+ binding site and the Gouy-Chapman theory of surface charge. This model gave similar estimates of negative surface charge density in the vicinity of the Ca2+ blocking site for muscle and heart Na+ channels. In contrast to other divalent cations listed above, Cd2+ and Zn2+ are more potent blockers of heart Na+ channels than muscle Na+ channels. Cd2+ induced a fast, voltage-dependent block in both Na+ channel subtypes with a 46-fold higher affinity at 0 mV for heart (KB = 0.37 mM) vs. muscle (KB = 17 mM). Zn2+ induced a fast, voltage-dependent block of muscle Na+ channels with low affinity (KB = 7.5 mM at 0 mV). In contrast, micromolar Zn2+ induced brief closures of heart Na+ channels that were resolved as discrete substate events at the single-channel level with an apparent blocking affinity of KB = 0.067 mM at 0 mV, or 110-fold higher affinity for Zn2+ compared with the muscle channel. High-affinity block of the heart channel by Cd2+ and Zn2+ exhibited approximately the same voltage dependence (e-fold per 60 mV) as low affinity block of the muscle subtype (e-fold per 54 mV), suggesting that the block occurs at structurally analogous sites in the two Na+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)

What's new in antibiotics?

Antibiotics are important agents in dermatologic practice. New drugs have expanded the therapeutic approach to uncomplicated skin infections and complicated infections involving deeper soft tissue or infections that require surgical intervention. This article reviews new antibiotics of dermatologic importance, including daptomycin (cyclic lipopeptide), linezolid (oxazolidinone), quinupristin-dalfopristin (streptogramins), moxifloxacin and gatifloxacin (fluoroquinolones), and dalbavancin and oritavancin, which are presently under investigation.

The emergence of methicillin-resistant Staphylococcus aureus in the community.

Infections with methicillin-resistant Staphylococcus aureus (MRSA), long endemic in hospitals and nursing homes, are now being reported in the community as well. While we await further epidemiological and microbiological study of this emerging pathogen, current clinical practice requires a reconsideration of the empiric use of beta-lactam agents for the seriously ill patient with a gram-positive infection.

Interleukin-1 beta production in dysthymia before and after pharmacotherapy.

BACKGROUND: Like major depression, dysthymia has been associated with elevated production of interleukin-1 (IL-1 beta) in mitogen-stimulated lymphocytes. In the present investigation, we assessed whether the elevated IL-1 beta production in dysthymic patients would normalize following treatment with sertraline. METHODS: The production of IL-1 beta was determined in dysthymic patients and in nondepressed control subjects. Patients then received 12 weeks of doses of either sertraline or placebo in a double-blind trial, after which cytokine production was again determined. RESULTS: Basal IL-1 beta was elevated in dysthymic patients relative to control subjects. Cytokine production was modestly correlated with the severity of symptoms and with the age of illness onset. Relative to placebo treatment, sertraline attenuated the symptoms of depression; however, this was not accompanied by normalization of IL-1 beta production. CONCLUSIONS: While dysthymia is associated with elevated IL-1 beta production, the failure for the cytokine to normalize following symptom alleviation suggests that either the IL-1 beta may be a trait marker of the illness, or that more sustained treatment is necessary to reduce cytokine production. Given the neuroendocrine and central neurochemical consequences of exogenously administered IL-1 beta, the possibility ought to be explored that increased IL-1 beta production may play a role in the pathophysiology of dysthymia.

Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder.

The effects of treatment with serotonin (5-HT) reuptake inhibitors on platelet 5-HT2 receptors, 5-HT reuptake sites an 5-HT uptake were studied in a double-blind trial comparing two selective serotonin reuptake inhibitors (SSRI), paroxetine, and fluoxetine, for the treatment of major depression. Hamilton Depression Rating Scale (HAM-D) scores and platelet 5-HT parameters were determined in 21 depressed patients at baseline, after 4 and 8 weeks of treatment, and were compared to 21 healthy controls. Antidepressant treatment did not significantly alter the density of 5-HT reuptake sites, labelled with [3H]paroxetine, or 5-HT2 receptors, labelled with [3H]LSD. However, a strong correlation was observed between the HAM-D suicidality item and 5-HT2 receptor density at baseline. A marked increase in platelet 5-HT2 receptors at baseline was observed in suicidal depressed patients compared to those with no suicidal ideation and healthy controls. Changes in [3H]paroxetine Bmax and in [3H]5-HT uptake significantly correlated with change in HAM-D score at 4 and 8 weeks respectively. These results confirm previous reports of an association between suicidality and platelet 5-HT2 receptor upregulation. Our data also lends support to the use of platelet 5-HT parameters as indicators of antidepressant efficacy, particularly in suicidal depressed patients.

The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects.

BACKGROUND: Efforts to model putative serotonergic deficits associated with affective disorders have frequently involved acute tryptophan depletion (ATD) as a manipulation strategy aimed at lowering brain serotonin synthesis. In an attempt to widen the scope of the measurement probes used in these investigations, the central actions of ATD and a subsequent dose of fenfluramine were examined via utilization of quantitative electroencephalography (EEG) and mood ratings. METHODS: Electroencephalograms (EEG) and subjective mood ratings were assessed in 28 healthy men before and after double-blind ingestion of a tryptophan-depleting (T-) amino acid mixture, or a nutritionally balanced (B) amino acid mixture containing tryptophan, and again after a single-blind oral dose of D,L-fenfluramine hydrochloride (60 mg). RESULTS: Compared to the B mixture, the T- mixture reduced total plasma tryptophan by more than 75% 5 hours after ingestion. Tryptophan depletion was associated with a modest lowering of mood and a slowing of EEG as indicated by increases in delta amplitude. Fenfluramine caused no change in mood but increased fast wave (beta) activity in anterior recordings when administered after the T-, but not after the B mixture. CONCLUSIONS: Quantitative EEG measurements may be a promising method for studying the central mechanisms underlying serotonin-mediated changes in mood and behavior.

Posttraumatic stress symptoms and salivary cortisol levels.

OBJECTIVE: This study assessed the relationship between posttraumatic stress symptoms and salivary cortisol levels after a severe ice storm. METHOD: Posttraumatic stress symptoms (Impact of Event Scale scores) and salivary cortisol levels were determined in 115 victims of an ice storm and in 27 healthy comparison subjects 1 month and approximately 1 year after the ice storm. RESULTS: One month after the storm, Impact of Event Scale scores for the victims (mean=20.31, SD=15.23) exceeded those of the comparison subjects (mean=5.30, SD=9.78) but were reduced approximately 1 year later (mean=14.01, SD=13.68). A quadratic relation was found to exist between Impact of Event Scale scores and cortisol levels. CONCLUSIONS: One month after the storm, cortisol levels were found to be elevated among the victims but were diminished among those with the highest Impact of Event Scale scores. This relationship was found not to exist approximately 1 year later.

Platelet alpha 2-adrenoreceptor binding in elderly depressed patients.

Specific binding of 3H-clonidine to platelet membranes was measured in depressed elderly patients and in an elderly control group. Maximum specific binding was significantly higher in depressed patients than in the control group, whereas the binding affinity was not significantly different.

Platelet serotonin measures in primary dysthymia.

Serotonergic function in 22 patients with primary dysthymia and 22 normal volunteers was evaluated by measuring [3H]serotonin uptake and [3H]paroxetine binding in platelets. A significantly lower maximum rate of serotonin uptake was noted in the dysthymic patients than in the normal subjects, indicating a possible serotonergic dysfunction in dysthymia. However, the values for parameters of paroxetine binding were similar in the two groups.

Treatment of primary dysthymia with group cognitive therapy and pharmacotherapy: clinical symptoms and functional impairments.

OBJECTIVE: This study assessed the efficacy of antidepressant treatment (sertraline) and group cognitive behavior therapy, alone or in combination, in primary dysthymia. The clinical features of dysthymia, as well as the functional impairments associated with the illness (e.g., quality of life, stress perception, coping styles), were evaluated. METHOD: Patients (N = 97) diagnosed with primary dysthymia, but no other current comorbid disorder, received either sertraline or placebo in a double-blind design over 12 weeks. In addition, a subgroup of the patients (N = 49) received a structured, weekly group cognitive behavior therapy intervention. RESULTS: Treatment with sertraline, with or without group cognitive behavior therapy, reduced the functional impairment of depression. The reductions were similar in the drug-cognitive therapy group and in subjects who received the drug alone. Furthermore, while group cognitive behavior therapy alone reduced the depression scores, this effect was not significantly greater than the effect of the placebo. The drug treatment also induced pronounced improvement in the functional measures, and in some respects these effects were augmented by group cognitive behavior therapy. Among patients who responded favorably to cognitive behavior therapy, the improvements in the functional measures were similar to those who responded to drug treatment, whereas such functional changes were not seen among patients who responded to placebo. CONCLUSIONS: Sertraline treatment effectively reduces the clinical symptoms and functional impairments associated with dysthymia. Although the group cognitive behavior therapy intervention was less effective in alleviating clinical symptoms, it augmented the effects of sertraline with respect to some functional changes, and in a subgroup of patients it attenuated the functional impairments characteristic of dysthymia.

Emphysematous urinoma in a renal transplant patient.

Urinary infection is a common complication after kidney transplantation. In some instances, especially with Escherichia coli infections, there is formation and collection of gas in the parenchyma and collecting system of the kidney, giving rise to the condition of emphysematous pyelonephritis. Such a process could occur in collections of urine (urinoma) secondary to ureteric leak in the transplant kidney. This process has not been described so far. In this report, we describe the first case of an infected urinoma with an interesting radiologic finding, a so-called emphysematous urinoma.

Synthesis and characterization of an aryl-azidoparoxetine. A novel photo-affinity probe for serotonin-transporter.

Paroxetine is an effective antidepressant drug and potent serotonin (5-HT) uptake inhibitor. It selectively labels 5-HT transporter on platelets and neurons. We report here the synthesis of an aryl-azido derivative of paroxetine, which is a novel photoactive and irreversible ligand for the [3H]paroxetine binding site on the platelet 5-HT transporter. The compound inhibited [3H]paroxetine binding (IC50, 55 nM) and 5-HT uptake (IC50, 12 nM) at equilibrium conditions and inactivated 10-20% of [3H]paroxetine binding sites upon irradiation at 320 nm. SDS-PAGE of platelet protein extract labelled with the radioactive analogue of the synthesized probe revealed the presence of four radioactive bands of which the 71-kDa one was the most prominent.

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.