Tadalafil - a therapeutic option in the management of BPH-LUTS.

BACKGROUND/AIMS: Men with signs of benign prostatic hyperplasia (BPH) may experience lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, intermittence, nocturia, straining, incomplete emptying or a weak urinary stream. The effective management of LUTS suggestive of BPH (BPH-LUTS) requires careful consideration of several factors, including the severity of a patient's symptoms, concurrent or other coexisting medical conditions, the ability to improve symptoms and impact quality of life (QOL), as well as the potential side effects of available treatment options. Several clinical studies have assessed phosphodiesterase type 5 (PDE5) inhibitors in reducing LUTS; however, tadalafil is the only PDE5 inhibitor approved for the treatment of signs and symptoms of BPH, as well as in men with both erectile dysfunction (ED) and the signs and symptoms of BPH. This review examined articles that assessed tadalafil in patients with signs and symptoms of BPH, with or without erectile dysfunction (ED), which led to regulatory approval in the United States and Europe. RESULTS: In dose-ranging and confirmatory studies, results demonstrate that tadalafil significantly improved total International Prostate Symptom Score (IPSS) following 12 weeks of treatment with once daily tadalafil 5 mg. Statistically significant improvements in Benign Prostatic Hyperplasia Impact Index (BII), IPSS subscores, IPSS QOL and International Index of Erectile Function (IIEF) were also observed. Improvement in urinary symptoms occurred regardless of age, previous treatment with an α1 -adrenergic blocker, BPH-LUTS severity at baseline or ED status. CONCLUSIONS: While tadalafil is most frequently recognised as a standard treatment option for men with ED, it also represents a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS.

Caregiver involvement in applied behavior-analytic research: A scoping review and discussion.

We conducted a scoping review to characterize the role of caregiver involvement in behavior-analytic research. We reviewed eight behavioral-learning journals from 2011-2022 for works that included children or caregivers as participants and characterized caregiver involvement as passive (implications for caregivers, input, social validity) and active (implementation, caregiver behavior, training, caregiver-collected data). The review identified 228 studies, and almost all (96.1%; n = 219) involved caregivers in some capacity; 94.3% (n = 215) had passive involvement (26.8% had only passive involvement; n = 61), 69.3% (n = 158) had active involvement (1.8% had only active involvement; n = 4), and 3.9% (n = 9) had neither passive nor active involvement. Involvement generally increased over publication years. The most common types of involvement were implications for caregivers, implementation, and input; caregiver-collected data were rare. We propose considerations when engaging caregivers in research and suggest new avenues of inquiry related to caregivers' treatment objectives and social validity, treatment implementers, and caregiver-collected data.

How to Administer the Performance Diagnostic Checklist-Human Services.

The Performance Diagnostic Checklist-Human Services (PDC-HS) is a performance analysis tool used to identify barriers to performance in human-service settings. Multiple published studies have used the PDC-HS to determine effective interventions (Wilder et al. Journal of Applied Behavior Analysis 53(2), 1170-1176, 2020). However, in a recent discussion article proposing guidelines for administering the PDC-HS, Brand et al. Behavior Analysis in Practice, 1-7 (2022) noted that procedural descriptions provided for administering the PDC-HS are somewhat ambiguous in the published literature. The purpose of the current systematic review was to compare methods used to administer the PDC-HS. Fifteen articles met inclusion criteria and were coded to evaluate commonalities among PDC-HS components. Authors generally agreed on how the outcomes of the PDC-HS were depicted and discussed but varied in their descriptions of methods used to administer the PDC-HS. Results are discussed in terms of the importance of technological descriptions and directions for future research towards the development of a more standardized tool. Supplementary Information: The online version contains supplementary material available at 10.1007/s40617-023-00848-3.

Assessing Parameters of Reinforcement on Efficiency of Acquisition: A Systematic Review.

Discrete-trial training (DTT) is a common method of instruction used in early intervention amongindividuals with autism spectrum disorder and related neurodevelopmental disorders and is an effective method of teaching different skills such as tacting, listener responding, and matching. Delivery of effective reinforcers is a key component of DTT. Although general recommendations have been made for effective reinforcement delivery in DTT, no review has synthesized the available research on the efficiency of various reinforcer parameters on efficiency of acquisition. The current systematic review assessed the efficiency of various reinforcer parameters on acquisition in DTT. Results were idiosyncratic, and a general paucity of repeated measures examining specific reinforcer parameters within and across studies was observed. In general, (1) maintaining high levels of treatment integrity, (2) delivery of tangible (i.e. leisure items) or edible reinforcers in comparison with contingent praise as a reinforcer, and (3) delivery of edible reinforcers in comparison with other topographies of reinforcement were the most successful reinforcer parameter manipulations and always resulted in more efficient skill acquisition. The results of this review provide clinicians with information regarding what reinforcer parameter manipulations may be more or less likely to support efficient acquisition. The present review also provides considerations and makes recommendations for future research.

Reducing control noise in gravitational wave detectors with interferometric local damping of suspended optics.

Control noise is a limiting factor in the low-frequency performance of the Advanced Laser Interferometer Gravitational-Wave Observatory (LIGO). In this paper, we model the effects of using new sensors called Homodyne Quadrature Interferometers (HoQIs) to control the suspension resonances. We show that if we were to use HoQIs, instead of the standard shadow sensors, we could suppress resonance peaks up to tenfold more while simultaneously reducing the noise injected by the damping system. Through a cascade of effects, this will reduce the resonant cross-coupling of the suspensions, allow for improved stability for feed-forward control, and result in improved sensitivity of the detectors in the 10-20 Hz band. This analysis shows that improved local sensors, such as HoQIs, should be used in current and future detectors to improve low-frequency performance.

Increasing selection of and engagement in physical activity in children with autism spectrum disorder.

Children with autism spectrum disorder (ASD) engage in reduced levels of physical activity relative to neurotypical children. Researchers conducted 2 studies to 1) evaluate the influence of the number of physical activity options and effort on choice and 2) develop a token-based intervention to increase physical activity engagement and evaluate whether the opportunity to access the intervention supported responding similar to physical or sedentary activity alone. Four children with ASD participated. Additional physical activity options alone did not increase physical activity selection, but increased effort reduced selection of sedentary activity. Tokens increased physical activity for 2 participants. A combination of physical and sedentary activities maintained as much as or more responding than either activity in isolation for all participants. Limitations and potential areas of future research on choice and physical activity are discussed.

Approaching the motional ground state of a 10-kg object.

The motion of a mechanical object, even a human-sized object, should be governed by the rules of quantum mechanics. Coaxing them into a quantum state is, however, difficult because the thermal environment masks any quantum signature of the object's motion. The thermal environment also masks the effects of proposed modifications of quantum mechanics at large mass scales. We prepared the center-of-mass motion of a 10-kilogram mechanical oscillator in a state with an average phonon occupation of 10.8. The reduction in temperature, from room temperature to 77 nanokelvin, is commensurate with an 11 orders-of-magnitude suppression of quantum back-action by feedback and a 13 orders-of-magnitude increase in the mass of an object prepared close to its motional ground state. Our approach will enable the possibility of probing gravity on massive quantum systems.

A Review on Functional Analyses of Tics.

Tic disorders are characterized by a class of responses assumed to be neurobiological in origin. Still, several studies have shown that tic frequency can be influenced by antecedent environmental events and social consequences. Prior reviews have summarized the effects of environmental events but have not examined relations between tic diagnosis, behavioral deficits (e.g., intellectual disability), tic topography, and the consequences observed to maintain tics. These variables might be important when attempting to predict or identify relevant consequences. A more thorough understanding of the variables that maintain and give rise to tics might also be useful in predicting responsiveness to treatment and intervention refinement. We reviewed and summarized results from the 13 attempts to experimentally identify maintaining consequences for tics (i.e., functional analyses) that have been published to date. We examined patterns of functions across tic diagnoses (i.e., Tourette's syndrome or not), communication impairments (i.e., an intellectual disability or reported language difficulty), and tic topography. Results suggested that individuals with Tourette's syndrome and those without communication impairments are more likely to have functional analysis outcomes consistent with automatic reinforcement, but exceptions in both directions highlight the utility of functional analysis in treating tics.

Ulysses dust measurements near Jupiter.

Submicrometer- to micrometer-sized particles were recorded by the Ulysses dust detector within 40 days of the Jupiter flyby. Nine impacts were recorded within 50 Jupiter radii with most of them recorded after closest approach. Three of these impacts are consistent with particles on prograde orbits around Jupiter and the rest are believed to have resulted from gravitationally focused interplanetary dust. From the ratio of the impact rate before the Jupiter flyby to the impact rate after the Jupiter flyby it is concluded that interplanetary dust particles at the distance of Jupiter move on mostly retrograde orbits. On 10 March 1992, Ulysses passed through an intense dust stream. The dust detector recorded 126 impacts within 26 hours. The stream particles were moving on highly inclined and apparently hyperbolic orbits with perihelion distances of >5 astronomical units. Interplanetary dust is lost rather quickly from the solar system through collisions and other mechanisms and must be almost continuously replenished to maintain observed abundances. Dust flux measurements, therefore, give evidence of the recent rates of production from sources such as comets, asteroids, and moons, as well as the possible presence of interstellar grains.

Dust measurements at high ecliptic latitudes.

Along Ulysses' path from Jupiter to the south ecliptic pole, the onboard dust detector measured a dust impact rate that varied slowly from 0.2 to 0.5 impacts per day. The dominant component of the dust flux arrived from an ecliptic latitude and longitude of 100 + 10 degrees and 280 degrees +/- 30 degrees which indicates an interstellar origin. An additional flux of small particles, which do not come from the interstellar direction and are unlikely to be zodiacal dust grains, appeared south of -45 degrees latitude. One explanation is that these particles are beta-meteoroids accelerated away from the sun by radiation pressure and electromagnetic forces.

The effects of exercise and calm interactions on in-kennel behavior of shelter dogs.

Over-activity, or excessive locomotion and barking in the kennel, may be unattractive to adopters and an indicator of poor welfare of kenneled dogs. The study assessed the efficacy of two common enrichment strategies, providing calm interaction and additional exercise, on in-kennel behavior in 16 shelter dogs. Both interventions resulted in appropriate behavior just prior to the sessions (t=2.10, df=7, p=0.03 and F [2216]=7.58, p=0.0007, respectively), but both also resulted in an increase of some undesirable behaviors immediately after the dogs were taken back to their kennels (F [3216]=7.77, p=0.0001 and F (5216)=10.1, p<0.0001 respectively). Right after receiving additional exercise, the dogs spent more time in back and forth motion in the kennel. Right after receiving the calm interaction, the dogs spent less time in the front of the kennel, less time facing forward, and more time engaging in back and forth motion. However, dogs also spent less time barking and jumping on the kennel door right after the calm interaction. The results suggest that both interventions may be useful, but shelter administrators and volunteers must take all of the behavioral changes into account when administering these interventions.

Pharmacokinetic analysis of 5-[18F]fluorouracil tissue concentrations measured with positron emission tomography in patients with liver metastases from colorectal adenocarcinoma.

The purpose of our study was to develop a pharmacokinetic model to quantify the intracellular 5-fluorouracil (5-FU) concentration in liver metastases, which is expected to be closely correlated to therapy response. In addition, the influence of the biomodulator folinic acid on the action of 5-FU in the metastases was investigated. After i.v. application of 5-FU labeled with the positron emitter fluorine-18 (5-[18F]FU), the kinetics of the regional 5-[18F]FU/uptake was measured dynamically with positron emission tomography over 120 min in 14 patients with a total of 27 liver metastases from colorectal adenocarcinoma. Activity-time curves were evaluated in the metastases, the normal liver tissue, as well as in the aorta and analyzed by a six-compartment model. The catabolic breakdown of 5-FU to alpha-fluoro-beta-alanine (FBAL) in the normal liver tissue was modeled to separate the catabolites from the cytostatic agent 5-[18F]FU and the active 5-[18F]fluorodeoxyuridine nucleotides. With our model, all measured activity-time courses could be described adequately with only small interindividual variations in parameters connected with liver and blood. Extrahepatic clearance of 5-FU was estimated as 0.66 +/- 0.33 liters/min, whereas the hepatic clearance was 0.52 +/- 0.25 liters/min. The Michaelis-Menten parameters describing the nonlinear conversion of 5-FU to FBAL were Km = 11.3 +/- 6.4 micromol and Vmax = 147.1 +/- 130.7 micromol/min. The maximum FBAL concentration in the liver was reached between 35 and 65 min after i.v. 5-FU infusion. The most sensitive parameters for therapy monitoring were k(in) and k(out), which characterize the transport in and out of the intracellular volume of the metastases, respectively. Tumor response can only be expected if k(in) is high and k(out) is low ("trapping"). These criteria were met by 6 of the 27 metastases, which were identical to those with high values for the area under the intracellular 5-FU concentration curve (AUC[meta,IC]5-FU). The parameters k(in) and k(out) were also used to investigate the influence of the biomodulating agent folinic acid on drug effect. Five of the six metastases that showed trapping belonged to patients who received folinic acid. With the exception of one patient, however, all patients who received folinic acid had multiple metastases, of which only one was able to trap 5-FU. Because patient response can only be expected when all metastases trap 5-FU, folinic acid showed no effect on the overall clinical response. With the quantitative modeling approach used, trapping of 5-FU can be assessed noninvasively and on an individual basis. This makes it possible to adjust the dose for each individual patient to optimize the treatment schedule.

The Advanced LIGO photon calibrators.

The two interferometers of the Laser Interferometry Gravitational-wave Observatory (LIGO) recently detected gravitational waves from the mergers of binary black hole systems. Accurate calibration of the output of these detectors was crucial for the observation of these events and the extraction of parameters of the sources. The principal tools used to calibrate the responses of the second-generation (Advanced) LIGO detectors to gravitational waves are systems based on radiation pressure and referred to as photon calibrators. These systems, which were completely redesigned for Advanced LIGO, include several significant upgrades that enable them to meet the calibration requirements of second-generation gravitational wave detectors in the new era of gravitational-wave astronomy. We report on the design, implementation, and operation of these Advanced LIGO photon calibrators that are currently providing fiducial displacements on the order of 10-18m/Hz with accuracy and precision of better than 1%.

Molecular cloning and expression of cDNA for rat pancreatic cholesterol esterase.

A full-length cDNA complementary to the rat pancreatic cholesterol esterase mRNA was isolated by screening a rat pancreatic cDNA expression library in lambda gt11 vector with antibodies against the porcine pancreatic cholesterol esterase. The isolated cholesterol esterase cDNA is 2050 bp in length and contains an open reading frame coding for a protein of 612 amino acids. A 20-amino acid hydrophobic leader sequence is predicted, based on the position of the first ATG initiation codon upstream from the sequenced amino terminus of the isolated cholesterol esterase. The cholesterol esterase cDNA was subcloned into a mammalian expression vector, pSVL, for transfection studies. Expression of the cDNA in COS cells resulted in the production of bile salt-stimulated cholesterol esterase. Comparison of the cholesterol esterase cDNA sequence with other proteins revealed that the pancreatic cholesterol esterase is identical to rat pancreatic lysophospholipase. The primary structure of cholesterol esterase displayed no significant homology with other lipases, although the putative lipid interfacial recognition site of G-X-S-X-G is present in the cholesterol esterase sequence. However, the cholesterol esterase sequence revealed a 63-amino-acid domain which is highly homologous to the active site domain of other serine esterases. These data suggest that cholesterol esterase may be a member of the serine esterase supergene family. Analysis of the cholesterol esterase structure also revealed a repetitive sequence enriched with Pro, Asp, Glu, Ser, and Thr residues at the C-terminal end of the protein. This sequence is reminiscent of the PEST-rich sequences in short-lived proteins, suggesting that cholesterol esterase may have a short half-life in vivo. Northern blot hybridization showed that the bile salt-stimulated cholesterol esterase mRNA is present in liver suggesting that this protein may also be synthesized by liver cells.

Sequence identity between human pancreatic cholesterol esterase and bile salt-stimulated milk lipase.

Three overlapping cDNA clones covering the entire primary sequence of the bile salt stimulated lipase in human milk were isolated from a human breast lambda gt10 cDNA library by screening with the rat pancreatic cholesterol esterase cDNA. Nucleotide sequencing of the cDNA showed that the human milk lipase mRNA encodes a 748-residue protein, including a 23-residue signal peptide. The human milk lipase cDNA is highly homologous to rat pancreatic cholesterol esterase, suggesting that the milk lipase may be identical to the cholesterol esterase in human pancreas. This conclusion was confirmed by isolation and sequencing of the cDNA for human pancreatic cholesterol esterase. Analysis of the sequence for the human cholesterol esterase/milk lipase revealed similarities to other serine esterases in three distinct regions of the protein. These domains may represent the active site triads of these proteins.

Magnetic resonance imaging in a case of autopsy-proved adult subacute necrotizing encephalomyelopathy (Leigh's disease).

Leigh's disease, or subacute necrotizing encephalomyelopathy (SNE), in adults is rare, and its diagnosis has depended on the postmortem identification of characteristic lesions in a typical distribution. We observed an autopsy-proved case of SNE in which the diagnosis was established by the distribution and evolution of lesions documented by serial magnetic resonance imaging (MRI). A 21-year-old woman insidiously developed diplopia and gait disturbance, and subsequently deteriorated to a vegetative state over seven months. An initial MRI obtained one month after presentation showed increased signal intensity that surrounded the aqueduct of Sylvius and involved the tectum of the midbrain. Serial MRI scans showed these lesions to extend and symmetrically involve the tectum of the midbrain, caudate, putamen, globus pallidus, and substantia nigra, while sparing the mammillary bodies and red nuclei. Despite treatment with 2 g of thiamine administered intravenously daily, she continued to deteriorate and died. Results of an autopsy established the diagnosis of SNE and confirmed the MRI-identified distribution of lesions. To our knowledge, this case is the first report of MRI findings in an adult with autopsy-proved SNE, suggesting that MRI can be valuable in the early diagnosis of this disease.

Central nervous system involvement in the eosinophilia-myalgia syndrome.

A patient with eosinophilia-myalgia syndrome developed progressive central nervosa system involvement that did not improve despite discontinuation of L-tryptophan therapy. Neurologic impairment was manifested initially by spastic monoparesis, which was improved by treatment with methyl-prednisolone and hydroxyurea. Recurrence of weakness was accompanied by gait ataxia, dysphagia, and complaints of a gradual decline in memory and concentration. Neuropsychological testing identified a broad pattern of cognitive deficits suggestive of a subcortical dementia, and magnetic resonance imaging demonstrated multiple high-signal lesions in the white matter. Cognitive deficits appear to be underrecognized in patients with the eosinophilia-myalgia syndrome. The response of our patient's initial symptoms to corticosteroid therapy suggests a possible role for autoimmune mechanisms in the pathogenesis of central nervous system involvement in the eosinophilia-myalgia syndrome. Neuropsychological evaluation should be performed in patients with cognitive complaints to delineate the full spectrum of central nervous system impairment associated with the eosinophilia-myalgia syndrome.

The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis.

Accumulating evidence indicates that a complement-mediated microvasculopathy may play a pathogenic role in dermatomyositis. In a previous study, we demonstrated neoantigens of the C5b-9 complement membrane attack complex in the muscle microvasculature of childhood and adult cases of dermatomyositis. To further characterize the relationship between the vascular complement deposits and histologic changes, quantitative histopathologic analyses were performed on 39 dermatomyositis biopsy specimens (26 adult, 13 children). There was a significant correlation between the percentage of fascicles with fibers having focal myofibrillar loss, a change seen early in the evolution of ischemic muscle fiber damage, and the percentage of fascicles having capillary deposits of membrane attack complex. Conversely, in biopsy specimens with a higher percentage of fascicles with perifascicular atrophy, membrane attack complex deposits were significantly less common. A fascicle-by-fascicle analysis supported these observations. Patients whose biopsy specimens were negative for microvascular membrane attack complex had clinical weakness for a significantly longer time than those patients with vascular complement deposits. These data support the hypothesis that the complement-mediated vasculopathy is a primary immunopathogenic event in the evolution of muscle lesions in dermatomyositis.

Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria.

Over a 10-year period, we followed up 60 patients (35 men and 25 women) with chronic inflammatory demyelinating polyradiculoneuropathy. Diagnosis was based on previously outlined criteria. Patients were treated in a uniform manner and the overwhelming majority, 56 (94.9%) of 59 treated patients, initially responded to immunosuppressive therapy. The time for initial improvement was 1.9 +/- 3.6 months while the time to reach a clinical plateau was 6.6 +/- 5.4 months. The course was monophasic in 32 patients (53.3%) and relapsing in 28 (46.6%). Despite the initial responsiveness, only 24 (40%) of 60 patients are in partial or complete remission, receiving no medication. Two patients died. We were unable to identify specific clinical or laboratory features at the time of diagnosis that predicted outcome. Our data analysis, along with previous reports, suggests that chronic inflammatory demyelinating polyradiculoneuropathy may be more heterogeneous than previously emphasized. In this light, we have proposed diagnostic criteria that allow for the heterogeneity but at the same time provide for a more consistent approach to better establish the natural history of this condition.