Considering formulation characteristics when prescribing and dispensing medicinal products for children: a qualitative study among GPs and pharmacists.

BACKGROUND: Finding appropriate medicinal product formulations and dosage forms for children can be challenging. Knowledge about considerations behind which medicinal product to prescribe or dispense for children is lacking. OBJECTIVE: To explore considerations of formulation characteristics of medicinal products made by GPs when prescribing and by pharmacists when dispensing medicines for children 0-6 years of age. METHOD: A qualitative study was performed by conducting three semi-structured focus groups with GPs and three with pharmacists, using nearly identical thematic interview guides. Analysis was performed using systematic text condensation. RESULTS: Both GPs and pharmacists considered whether children and parents were willing and able to use medicinal products such as tablets and poor-tasting liquids before prescribing and dispensing them. These considerations were commonly based on health care workers' prior experiences, although parents and sometimes children were asked about their experiences with solid formulations. For antibiotics, GPs primarily wanted to prescribe first-choice antibiotics according to guidelines. Parents' concerns about getting the child to take the medicinal product due to poor taste could lead to the prescription of second-choice antibiotics. The pharmacists sometimes changed the prescribed formulation at parents' request but never changed the type of antibiotic without contacting the prescriber. CONCLUSION: Formulation characteristics strongly influenced which medicinal product children were prescribed and dispensed. Individualizing formulation choices for children through an increased collaboration between physicians, pharmacists and parents is suggested.

Register-based study showed that the age when children were prescribed antibiotic tablets and capsules instead of liquids increased from 2004 to 2016.

AIM: We investigated the age when the prescriptions of oral antibiotic formulations for children from birth to 12 years of age changed from being mostly liquid to mostly solid and the associations between solid formulations and child, prescriber and medication characteristics. METHODS: This register-based study comprised data from the Norwegian Prescription Database on oral antibiotics dispensed between 2004 and 2016 when both solid and liquid dosage forms were available in appropriate doses. RESULTS: Just over 1.2 million prescriptions were studied, and the age when children were prescribed oral solid antibiotics gradually increased. The mean age of conversion from liquids to solid formulations was 6.9 years and ranged from 5.7 years in 2004/2005 to 7.9 years in 2015/2016. Patient factors associated with solid dosage forms were the children's increasing age and male gender. Practitioner factors were the prescribers' increasing age, male gender, being a general practitioner and issuing fewer than 23 paediatric antibiotic prescriptions per year. Medication factors were bad-tasting liquids and the size and shape of solid dosage forms. CONCLUSION: The age when children were prescribed antibiotic tablets and capsules increased from 2004 to 2016. The medicine characteristics were quite consistent, so this was probably caused by a shift in formulation preferences.

Requests for new oral antibiotic prescriptions in children within 2 days: a Norwegian population-based study.

Background: Children commonly refuse to take antibiotics, which may induce parents to request new antibiotic prescriptions with different pharmaceutical characteristics. Objectives: To investigate prescription changes for children 0-12 years receiving oral liquid or solid antibiotic formulations and to explore the relationships between prescription changes and characteristics related to the child, prescriber and antibiotic. Methods: A population-based registry study based on data from the Norwegian Prescription Database (NorPD) from 2004 to 2016. Antibiotic prescription changes were defined as the dispensing of subsequent antibiotics with different pharmaceutical characteristics to the same child within 2 days after initial prescriptions. Data were analysed using multivariable logistic regression and generalized estimating equations. Results: Requests for new prescriptions followed 3.0% of 2 691 483 initial antibiotic prescriptions for children. Young children who received solid formulations (10.9%) and certain poor-tasting antibiotics (8.6%) had the highest proportions of new prescriptions. Penicillin V was most commonly changed, while macrolides/lincosamides dominated subsequent prescriptions. In order of magnitude, the characteristics associated with requests for new prescriptions were the children's ages, poor taste and concentration of liquids, size and shape of solids, prescribers born in recent decades, and girl patients. Reimbursed prescriptions and scored solids were associated with fewer requests. Conclusions: While only 3% of the antibiotic prescriptions were changed, the preference of broad-spectrum over narrow-spectrum antibiotics for young children in this study mirrors international prescription patterns. Avoiding the costs of children's refusal and consequent changes may thus be a motivation for choosing more preferred antibiotics.

Fear of hypoglycaemia and its relation to hypoglycaemia awareness and symptom intensity in Type 1 diabetes.

AIMS: To investigate fear of hypoglycaemia (FoH) in relation to hypoglycaemia awareness, history of severe hypoglycaemia (SH) and hypoglycaemia symptoms in adults with Type 1 diabetes. METHODS: Questionnaire-based cross-sectional survey. We assessed FoH with the Hypoglycaemia Fear Survey-II Worry subscale, hypoglycaemia awareness status with the Gold score, and used the Edinburgh Hypoglycaemia Scale to grade the presence and intensity of hypoglycaemia symptoms. All these measures have previously been validated for research application. We used multivariable linear regression to examine associations between FoH and hypoglycaemia awareness status, history of SH and hypoglycaemia symptom score. RESULTS: Of 636 invitees, 445 (70%) responded, with 435 responses eligible for analyses. Seventy-four persons had IAH (17%). Among those, 47 (64%) reported ≥ 1 SH during the preceding year, in contrast to this being reported by 113 (31%) of persons with normal awareness. The mean (SD) FoH worry score was 1.33 (0.78). This score was 0.64 (95% CI, 0.45-0.83) higher among people with impaired vs. normal hypoglycaemia awareness and 0.53 (95% CI, 0.33-0.73) higher among people with ≥ 3 episodes of SH the preceding year vs. people with no such episode. A higher number and intensity of hypoglycaemia symptoms was associated with higher FoH, as demonstrated by an increase in mean FoH worry score of 0.30 (95% CI, 0.23-0.36) per point increase in mean Edinburgh hypoglycaemia score. CONCLUSIONS: Impaired awareness of hypoglycaemia, history of SH and higher Edinburgh hypoglycaemia scores were all associated with increased FoH in adults with Type 1 diabetes.

Reduced Th22 cell proportion and prevention of atopic dermatitis in infants following maternal probiotic supplementation.

BACKGROUND: In the randomized, controlled study Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT), maternal probiotic supplementation reduced the incidence of atopic dermatitis (AD) in the offspring. In the current study, we hypothesized that the effect was mediated by a shift in the T helper (Th) cells in the children. OBJECTIVE: To examine whether Th cell proportions were affected by maternal probiotic supplementation and thus could mediate the preventive effect of probiotics on AD. METHODS: A total of 415 pregnant women were randomized to ingest a combination of Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis subsp. lactis Bb-12 (Bb-12) and Lactobacillus acidophilus La-5 (La-5) or placebo, and their offspring were assessed for AD during the first 2 years of life. Peripheral blood collected at 3 months of age was analysed for regulatory T cells (n=140) and Th subsets (n=77) including Th1, Th2, Th9, Th17 and Th22. RESULTS: The proportion of Th22 cells was reduced in children in the probiotic group compared to the placebo group (median 0.038% vs 0.064%, P=.009). The difference between the probiotic and placebo groups was also observed in the children who did not develop AD during the 2-year follow-up. The proportion of Th22 cells was increased in children who developed AD compared to the children who did not develop AD (0.090% vs 0.044%, P<.001). Mediation analysis indicated that the preventive effect of probiotics was partially mediated through the reduction in Th22 cells. CONCLUSION: Perinatal maternal probiotic supplementation with a combination of LGG, Bb-12 and La-5 reduced the proportion of Th22 cells in 3-month-old children. This may partially explain the preventive effect of probiotics on AD.

Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin.

Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8-809) compared with healthy controls (median 110 pg/ml, range 8-359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma.

Prostate cancer detection: the value of performing an MRI before a biopsy.

BACKGROUND: In recent years, prostate-specific antigen (PSA) screening has been widely performed. As a result, patients who need to undergo a complete physical examination for an elevated PSA level have been rapidly increasing. Magnetic resonance imaging (MRI) examination has previously been reported to be effective for the detection of prostate cancer. PURPOSE: To evaluate the detectability of prostate cancer by performing MRI before biopsy, and to evaluate the relationship between detectability with MRI and cancer location, Gleason score (GS), and tumor size. MATERIAL AND METHODS: MRI was performed at 1.5 Tesla in 122 consecutive patients before biopsy. The detectability of prostate cancer, including sensitivity and positive predictive value (PPV) of transrectal ultrasonography (TRUS), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI) (b=2000 s/mm(2)), apparent diffusion coefficient (ADC) map, and biopsy, was calculated using whole-mount section histopathology as a gold standard. In addition, the relationship between the detectability on each MRI sequence and factors such as cancer location (peripheral zone vs. transition zone), GS 5-10, short-axis diameter (< or =4 mm, 5-9 mm, > or =10 mm), and long-axis diameter (< or =9 mm, 10-19 mm, > or =20 mm) were also evaluated. RESULTS: The sensitivities of TRUS, T2WI, DWI, ADC map, and biopsy were 26.9%, 41.2%, 56.7%, 57.7%, and 75.1%, respectively, and the PPVs of those modalities were 73.0%, 83.0%, 86.4%, 87.2%, and 91.5%, respectively. There was no correlation between the sensitivity of each MRI sequence and cancer location. The sensitivity of each MRI sequence increased as GS and short- and long-axis diameters of cancer lesions increased. CONCLUSION: MRI before a biopsy has a high detectability of prostate cancer, particularly with tumor size of more than 5 mm in short-axis diameter or 10 mm in long-axis diameter.

Evaluation of coronal CT findings of rare cases of isolated medial orbital wall blow-out fractures.

OBJECTIVES: To report rare cases of isolated medial orbital wall blow-out fractures and to evaluate their coronal CT findings. METHODS: Nine cases of medial orbital wall blow-out fractures, diagnosed by coronal CT in a general medical hospital between 1995 and 1999, were studied. CT was performed using direct coronal acquisition with a slice thickness of 5 mm. Images were obtained at bone window settings. Clinical examination findings from the medical records were used to give information on the cause of injury, ocular symptoms and the days after injury that the CT examination was performed. RESULTS: Most of the patients (67%) were young male adults. The cause of injury was most frequently the result of fist fighting or athletics (78%). Diplopia and/or limitation of the gaze were the main ocular symptoms (78%). The average time from injury to CT examination was 4 days (range 0-16 days). Seven of the nine patients with medial orbital wall fractures had isolated medial orbital wall blow-out fractures. Herniation of orbital contents toward the ethmoid sinus was observed among all nine fractures. Only three patients (33%) had a swelling and/or medial deviation of the medial rectus muscle, all three having isolated medial orbital wall blow-out fractures. CONCLUSIONS: Nine cases of medial orbital wall blow-out fractures were examined, seven of which were isolated medial wall blow-out fractures. CT findings of this type of fracture included herniation of the orbital contents toward the ethmoid sinus. However, swelling and/or medial deviation of the medial rectus muscle was also seen.

Ipsilesional biases in saccades but not perception after lesions of the human inferior parietal lobule.

We examined the effects of chronic unilateral lesions to either the inferior parietal lobe, or to the dorsolateral prefrontal cortex including the frontal eye fields (FEFs), upon human visual perception and saccades in temporal-order-judgment (TOJ) tasks. Two visual events were presented on each trial, one in each hemifield at various stimulus onset asynchronies (SOAs). In the saccade task, patients moved their eyes to whichever stimulus attracted gaze first. In the perceptual-manual task, they pressed a button to indicate which stimulus was perceived first. Frontal patients showed appropriate TOJs for visual targets in both tasks. Parietal patients showed appropriate TOJs in the perceptual-manual but not the saccade task; their saccades tended to be ipsilesional unless the contralesional target led substantially. This reveals a bias in saccade choice after parietal damage that cannot be attributed to deficient visual perception. These results challenge previous claims that only anterior lesions produce motoric spatial biases in humans. However, they are in accord with recent neurophysiological evidence for parietal involvement in saccade generation, and also with suggestions that visuomotor transformations in the parietal lobe serving direct spatial motor responses can dissociate from conscious perception as indicated by indirect arbitrary responses.

Changing faces: a detection advantage in the flicker paradigm.

Observers seem surprisingly poor at detecting changes in images following a large transient or flicker. In this study, we compared this change blindness phenomenon between human faces and other common objects (e.g., clothes). We found that changes were detected far more rapidly and accurately in faces than in other objects. This advantage for faces, however, was found only for upright faces in multiple-object arrays, and was completely eliminated when displays showed one photograph only or when the pictures were inverted. These results suggest a special role for faces in competition for visual attention, and provide support for previous claims that human faces are processed differently than stimuli that may be of less biological significance.

Malignant rhabdoid tumor: A phenotype? An entity?--A controversy revisited.

The term malignant rhabdoid tumor (MRT) has been used to describe a heterogeneous group of neoplasms, having in common distinct so-called "rhabdoid" cytologic features. The recent discovery of a candidate tumor suppressor gene for MRT, INI1 on chromosome (Ch)22q11.2, has re-established this neoplasm as a distinct entity. Malignant rhabdoid tumor may arise either de novo from nonneoplastic cells or through tumor progression from other types of neoplasms. These latter tumors, in which other nonrhabdoid tumor components are identified, may be termed composite MRT. In order to avoid misdiagnosing MRT as other types of neoplasia, one must keep in mind three distinct clinicopathologic features--young age of onset, variable histologic and immunohistochemical patterns, and an aggressive infiltrative character. In difficult cases, cytogenetics, fluorescence in situ hybridization (FISH), and molecular genetic analysis may assist in diagnosing MRT.

Inhibition of return in saccadic eye movements.

Inhibition of return (IOR) is a phenomenon in which responses generated to targets at previously attended locations are delayed. It has been suggested that IOR affords a mechanism for optimizing the inspection of novel locations and that it is generated by oculomotor reflexes mediated by the superior colliculus. In this investigation, we measured the effects of IOR on the metrics of saccadic eye movements made to novel and previously attended locations. Saccades made to cued target locations, as well as to other targets within the same hemifield, had longer latencies than saccades made towards the novel, uncued hemifield. We further found that the amplitudes of saccades towards the cued hemifield were more hypometric, but only when the amplitude could not be pre-programmed. These results provide evidence that IOR influences spatial, as well as temporal, parameters of saccadic eye movements and suggest that the exogenous orienting of attention, in addition to influencing target detection, also influences oculomotor programming.

Aneurysmal bone cyst of the coronoid process of the mandible.

A rare case of an aneurysmal bone cyst (ABC) involving the right coronoid process of the mandible in a 12-year-old girl is presented. The characteristic features with fluid-fluid levels within the lesion observed on Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) was helpful in the preoperative diagnosis.

Components of reflexive visual orienting to moving objects.

Posner and Cohen (1984) and Maylor (1985) initially observed that a luminance change produces both facilitatory and inhibitory effects on subsequent detection. While Posner and Cohen claimed that the facilitatory effect was mapped in retinotopic coordinates, they showed that inhibition of return (IOR) was mapped in "environmental coordinates." Tipper and colleagues (Tipper, Driver, & Weaver, 1991; Tipper et al., 1997; Tipper, Weaver, Jerreat, & Burak, 1994) and Abrams and Dobkin (1994b) have recently reported that IOR can be object based, but contradictory results have also been reported (Müller & von Mühlenen, 1996). Here we report six experiments showing that an uninformative peripheral cue can generate either facilitatory or inhibitory object-based effects that can tag moving objects and that can persist for several hundred milliseconds. Although the boundary conditions determining which effect will be manifest remain to be defined, the present results suggest that facilitation and inhibition are generated independently, rather than being components of the same biphasic process.

Interactions between color and word processing in a flanker task.

To examine interactions between color and word attributes, participants responded, either manually or vocally, to a central target (color patch or word) flanked by a Stroop stimulus. Color and word attributes of the flanker affected both vocal and manual responding to color patches. Color and word flankers also affected manual responding to word targets, but only word flanker affected vocal responding to word targets. These results are not consistent with models (e.g., translational models) of Stroop tasks, which posit that interactions between colors and words occur only when vocal responding is required.

Localization of the human frontal eye fields and motor hand area with transcranial magnetic stimulation and magnetic resonance imaging.

We localized the neuroanatomical correlates for control of saccadic eye movements and for finger movements using a combined transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) approach. Two participants underwent TMS while performing an endogenous saccade task. The motor hand area was localized by TMS and the region anterior to it was mapped to identify the borders of a region where TMS produced delays in generating contralateral saccades. MRI scans were then obtained with fiducial markers placed over the motor hand area and 2 cm anterior to it, the common cortical region that produced saccadic delays in these two subjects. It was also shown that the structural anatomy of the hand area, physiologically defined by visible contractions of the contralateral hand following TMS, corresponded to the knob-like structure recently reported [18, 19]. These results demonstrate that TMS can be a precise, non-invasive tool for neuroanatomical mapping of cortical structures when combined with structural images of the brain.

Response channel activation and the temporoparietal junction.

When we learn to make one motor response to one visual stimulus and a different motor response to another, representations of these stimulus-response associations must be maintained to efficiently transduce perception into action. When an irrelevant distractor is presented adjacent to a target stimulus, interference is observed when the two stimuli are associated with conflicting responses, presumably due to response channel activation by the incompatible information. We have explored the neural bases of these interference effects. In a previous study, patients with hemispatial neglect showed normal interference from contralesional flankers. In another study, patients with lesions of the lateral prefrontal cortex were found not to show interference from distractors presented in the contralesional hemifield. The current study provided a more anatomically detailed investigation of the effects of posterior association cortex lesions on flanker interference. Patients with chronic, unilateral lesions involving the temporoparietal junction (TPJ), two of whom had hemispatial neglect, were compared with patients with lesions of the posterior association cortex not involving the TPJ. All patients performed a color discrimination task at fixation while a congruent or incongruent colored flanker was briefly presented (16.7 ms) in the adjacent contralesional or ipsilesional hemifield. Patients with TPJ lesions showed no interference effects from the contralesional flankers. These results suggest that the TPJ, in combination with the dorsolateral prefrontal cortex, is involved in transducing perception into action.

Object-based facilitation and inhibition from visual orienting in the human split-brain.

Object-based attention was examined in 2 split-brain patients. A precued object could move within a visual field or cross the midline to the opposite field. Normal individuals show an inhibition in detecting signals in the cued object whether it moves within or between fields. Both patients showed this effect when the cued object moved within a visual field. When it crossed the midline into the opposite visual field, however, detection was faster in the cued box. These results reveal both facilitatory and inhibitory effects on attention that are object based and may last for several hundred milliseconds. However, the inhibition requires an intact corpus callosum for interhemispheric transfer, whereas the facilitation is transferred subcortically.

Helical CT evaluation of arterial invasion in pancreatic tumors: comparison with angiography.

BACKGROUND: Although helical computed tomography (HCT) has been widely employed for the evaluation of pancreatic tumors, its capability in the diagnosis of peripancreatic arterial invasion has not been established. METHODS: HCT with a sequential cine-display was carried out in 34 patients with solid pancreatic tumors and 28 control subjects without angiographic abnormality. The HCT scans were compared with angiograms. RESULTS: All major arteries (celiac, superior mesenteric, splenic, gastroduodenal) and superoanterior pancreaticoduodenal arteries were well demonstrated by HCT in control subjects. However, posterior pancreaticoduodenal arcades and other smaller arteries were poorly identified. Although 19 major arterial invasions were equally diagnosed by HCT and angiography in patients with pancreatic tumors, only 4 of 11 minor arterial invasions were correctly diagnosed by HCT. CONCLUSIONS: Although HCT has some limitations in the evaluation of minor peripancreatic arteries, it can provide enough information for making a decision about conducting pancreatic surgery.

Transcranial magnetic stimulation of the prefrontal cortex delays contralateral endogenous saccades.

The contributions of the superior prefrontal cortex (SPFC) and the superior parietal lobule (SPL) in generating voluntary endogenous and reflexive visually guided saccades were investigated using transcranial magnetic stimulation (TMS). Subjects made choice saccades to the left or right visual field in response to a central arrowhead (endogenous go signal) or a peripheral asterisk (exogenous go signal) that were presented along with a single TMS pulse at varying temporal intervals. TMS over the SPFC increased latencies for saccades made in response to an endogenous go signal toward the contralateral hemifield. No effects were observed when the go signal was exogenous and TMS was over the SPFC or when TMS was over the SPL for either saccade type. The delayed contralateral endogenous saccades observed in this study are likely a consequence of disruption in the normal operations of the human frontal eye field.