TONI - One for all? Participatory development of a transtheoretic and transdiagnostic online intervention for blended care.

Background: Internet-based interventions offer a way to meet the high demand for psychological support. However, this setting also has disadvantages, such as the lack of personal contact and the limited ability to respond to crises. Blended care combines Internet-based interventions with face-to-face psychotherapy and merges the benefits of both settings. To ensure the uptake of blended care in routine care, Internet-based interventions need to be suitable for different therapeutic approaches and mental disorders. Objective: This paper describes the participatory development process of the Internet-based intervention "TONI" using a common therapeutic language and content on various transdiagnostic topics to be integrated into routine outpatient psychotherapy. Methods: To develop this intervention in a participatory manner, we followed the Integrate, Design, Assess, and Share (IDEAS) framework. In a multilevel development process, we used a combination of interviews, focus groups, and proofreading to optimally tailor online modules to routine outpatient psychotherapy. Building on well-established cognitive-behavioral online content, we included expert interviews with psychodynamic (n = 20) and systemic psychotherapists (n = 9) as well as focus groups with psychotherapists of different approaches (n = 10) and persons with lived experience of mental illness (PWLE; n = 10). Results: We describe the development process of TONI step-by-step, outlining the specific requirements that therapists from different therapeutic approaches as well as PWLE have and how we implemented them in our intervention. This includes the content and specific exercises in the online modules, aspects of data protection, language, design, and usability. Conclusion: Internet-based interventions that use a common therapeutic language and address therapeutic principles across different approaches have the potential to advance digitalization in psychotherapy. Involving psychotherapists and PWLE in intervention development may positively impact acceptance and usage in practice. This study shows how participatory intervention development involving both psychotherapists and PWLE can be carried out.

Retrospective study of the incidence of sarcoidosis-like reaction in patients treated with immunotherapy.

AIM: To assess the frequency of radiographically evident drug-induced sarcoidosis-like reaction (DISR) in patients treated with anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) therapy, anti-programmed cell death protein 1 (PD-1) therapy, or a combination of both in a single centre. MATERIALS AND METHODS: The images and medical records of 457 patients with metastatic melanoma or head and neck cancer treated with either anti-CTLA-4 therapy, anti-PD-1 therapy, or a combination of both at University of California medical centre were reviewed retrospectively and the incidence of radiological manifestations of DISR was assessed among these treatment groups. RESULTS: Radiological manifestations of DISR were found in 19/457 patients (4.1%). The mean interval from the initiation of immunotherapy to development of DISR was 5.5 months (range 2.3-13.5 months). Mean interval from radiological detection of DISR to imaging evidence of resolution was 5.8 months (range 1.6-18.3 months). Three patients out of 81 (3.7%), 11/297 (3.7%), and 5/79 (6.3%) developed sarcoidosis-like reaction after treatment with anti-CTLA-4 antibody, anti-PD-1 antibody, and a combination of both, respectively. Most patients with DISR were asymptomatic and did not require systemic therapy. Most patients did not demonstrate concomitant increased maximum standardised uptake value (SUVmax) in other organs on their integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT). CONCLUSIONS: In the present retrospective study of patients treated with immune checkpoint inhibitors (ICIs), DISR occurred in approximately 3.7% of patients treated with either anti-CTLA-4 or anti-PD-1 antibody and 6.3% of patients treated with a combination of both.

Surgical techniques used in the management of intra-arachnoid diverticula in dogs across four referral centres and their immediate outcome.

OBJECTIVES: To report the surgical techniques being used to treat single focal spinal intra-arachnoid diverticula in dogs, their complications and immediate postoperative outcomes. MATERIALS AND METHODS: Retrospective multi-centre case series across four referral centres. RESULTS: Fifty-seven dogs were included in the study. The most common type of surgery was durectomy (28 dogs) followed by marsupialisation (11 dogs), durotomy alone (seven dogs), shunt placement (six dogs) and stabilisation (five dogs). A higher proportion of intra-arachnoid shunt dogs became unable to walk in the immediate postoperative period (24 hours postsurgery) (4/6, 66%) compared to all dogs five of 57, 9% (2/7 durotomy alone, 3/28 durectomy alone). Of the nine dogs with immediate postoperative deterioration, seven had improved, walking without assistance, by 3 to 5 weeks postoperatively. CLINICAL SIGNIFICANCE: This study does not identify an influence of surgical technique on short-term outcome. Dogs with a thoracolumbar intra-arachnoid diverticulum that undergo a shunt placement are likely to deteriorate neurologically in the immediate 24-hour postoperative period but appear to improve by 3 to 5 weeks after surgery. Further work is required to evaluate whether one surgical technique is superior for preventing or reducing long-term relapse.

Comparison of basal insulin therapies with regard to the risk of acute myocardial infarction in patients with type 2 diabetes: an observational cohort study.

AIMS: To assess the risk of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus treated with long-acting insulin analogues in comparison with other basal insulin therapy. METHODS: We used German insurance claims data from the years 2004-2009 to conduct a study in a retrospective cohort of patients with type 2 diabetes. Naïve insulin users were defined as patients who had an insulin-free history before the first prescription of long-acting analogue insulin, human NPH insulin or premixed insulin and who were pretreated with oral antidiabetic drugs. Adjusted hazard ratios (HRs) of AMI and corresponding 95% confidence intervals (CIs) were calculated using sex-stratified Cox models. Propensity-score-matched analyses were conducted as sensitivity analyses. RESULTS: We identified 21,501 new insulin users. Patients treated with premixed insulin were older than patients treated with analogue or NPH insulin (mean age 70.7 vs. 64.1 and 61.6 years, respectively) and had more comorbidities. Regarding the risk of AMI, adjusted HRs showed no statistically significant difference between NPH and analogue insulin (HR 0.94, 95% CI 0.74-1.19), but a higher risk for premixed than for analogue insulin (HR 1.27, 95% CI 1.02-1.58). Contrary to the primary analysis, the propensity-score-matched analysis did not show an increased risk for premixed insulin. CONCLUSIONS: In contrast to a former database study, no difference was observed for the risk of AMI between long-acting analogue and NPH insulin in this study. Neither long-acting analogue insulin nor premixed insulin appears to be associated with AMI in patients with type 2 diabetes.

The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial.

BACKGROUND: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. METHODS: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. RESULTS: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations. CONCLUSIONS: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.

Cervical intervertebral foraminal disc extrusion in dogs: clinical presentation, MRI characteristics and outcome after medical management.

The aim of the present study was to retrospectively evaluate the clinical signs, MRI characteristics, interobserver agreement and outcome after medical treatment in dogs affected by cervical intervertebral foraminal disc extrusion (CIFDE). The medical records of three referral institutions were searched for dogs diagnosed with CIFDE between 2010 and 2012. Thirteen dogs were identified with CIFDE; affected dogs often had a normal neurological examination, with cervical hyperaesthesia and lameness as the most common clinical signs. On MRI, sagittal images showed no evidence of compression of the spinal cord; CIFDE could be identified only on transverse sections in all cases. An excellent interobserver agreement was found in the localisation of the affected intervertebral disc space, and a substantial agreement was found on the detection of CIFDE versus foraminal stenosis caused by overgrowing articular processes. All but two dogs recovered completely, and they were considered free of clinical signs without analgesia within a median of 7.5 weeks (range: 2-20) after medical management was started. The remaining two dogs were surgically treated followed by complete recovery. In view of our findings, the importance of a thorough MRI investigation in dogs presenting with cervical hyperaesthesia as the sole clinical sign should be highlighted.

Diagnosis of Cardiac Metastasis from Endometrial Cancer by F-18 FDG-PET/CT.

We report a case of a 59-year-old woman with right ventricular metastasis of undifferentiated endometrial cancer. Cardiac metastasis from endometrial cancer is a very rare finding. The case demonstrates that undifferentiated endometrial cancer is capable of metastasizing, presumably through a hematogenous route, to unexpected distant organs. These unexpected sites should not be undermined in the restaging and surveillance of these patients.

Idiopathic hypertrophic pachymeningitis in six dogs: MRI, CSF and histological findings, treatment and outcome.

Idiopathic hypertrophic pachymeningitis has been described in humans as a rare, chronic progressive non-specific inflammatory and fibrotic disease of the dura mater. This is a case series of six canine cases of presumptive or confirmed intracranial idiopathic hypertrophic pachymeningitis. These dogs were included in this retrospective study, based on magnetic resonance imaging findings. All presented with pachymeningeal thickening and enhancement without involvement of the leptomeninges on magnetic resonance imaging and no underlying cause identified on cerebrospinal fluid analysis, complete blood count, serum biochemistry and infectious disease titres. Histopathological examination was available in one case. Response to immunomodulatory treatment (corticosteroids and cytosine arabinoside) was achieved in five cases. Idiopathic hypertrophic pachymeningitis should be considered as a possible differential diagnosis for dogs with pachymeningeal thickening on magnetic resonance imaging and no identified underlying cause. The prognosis appears to be fair to poor.

Porencephaly and hydranencephaly in six dogs.

A retrospective study was performed to identify dogs with cerebrospinal fluid-filled cavitatory lesions on MRI. Six dogs were included and the lesions were classified. In the three dogs in the present study with hydranencephaly, unilateral but complete loss of the temporal and parietal lobes was noted and had almost complete loss of the occipital and frontal lobes of a cerebral hemisphere. In the three dogs with porencephaly, there was unilateral incomplete loss of the parietal lobe and one dog had additional partial loss of the temporal and frontal lobes. Two of the dogs with porencephaly had seizures; the third showed no associated clinical signs. The dogs with hydranencephaly had mentation changes and circled compulsively. The two porencephalic dogs with seizures were treated with phenobarbitone. One of the dogs with hydranencephaly showed increased frequency and duration of circling; one dog's clinical signs did not progress and the third dog was euthanased due to increasing aggression. The dog with increased circling had ventriculoperitoneal shunt placement and the circling frequency reduced.

A novel movement disorder in related male Labrador Retrievers characterized by extreme generalized muscular stiffness.

OBJECTIVES: To describe the clinical phenotype of a new motor disorder in Labrador Retrievers. ANIMALS AND METHODS: Case series study. Seven young male Labrador Retrievers presented for evaluation of stiff gait. RESULTS: All affected dogs had generalized muscular stiffness, persistent at rest and resulting in restricted joint movements. They showed a forward flexed posture, festinating gait, and bradykinesia. Signs developed between 2 and 16 months of age and tended to stabilize in adulthood. Needle electromyogram in the conscious state showed continuous motor unit activity in resting epaxial and proximal limb muscles. This activity was abolished by general anesthesia. Muscle and nerve histopathology was normal. In 2 dogs necropsied, astrocytosis was evident throughout the spinal cord gray matter, reticular formation and caudate nuclei. Decreased neuronal counts were selectively found in the spinal cord Rexed's lamina VII, but not in VIII and IX. Pedigree analysis showed that the affected dogs were from 5 related litters. CONCLUSIONS AND CLINICAL IMPORTANCE: This new hypertonicity syndrome in Labrador Retrievers is unique because of the selective distribution of the histological lesions, the lack of progression in adulthood, and its exclusive occurrence in male dogs. Pedigree analysis suggests an X-linked hereditary disease, although other modes of inheritance cannot be ruled out with certainty. We hypothesize that altered output from basal nuclei and reticular formation together with motor neuron disinhibition caused by a decreased number of spinal cord interneurons leads to the muscular stiffness.

[18F] Fluorodeoxyglucose positron-emission tomography-CT imaging of carotidynia.

Carotidynia is an idiopathic syndrome characterized by pain over the carotid bifurcation without associated luminal pathologic process. The classification of carotidynia as a distinct disease rather than as a symptom has generated controversy in the literature. Recent reports, however, suggest that carotidynia is a distinct disease characterized by the presence of enhancing soft tissue in the carotid sheath. We describe findings of carotidynia on positron-emission tomography and CT that further support the classification of carotidynia as a distinct inflammatory disease.

Treatment of 11 dogs with meningoencephalomyelitis of unknown origin with a combination of prednisolone and cytosine arabinoside.

The records of 11 dogs with evidence of meningoencephalomyelitis of unknown origin were reviewed. Two of them had had a focal form of the disease and the other nine a disseminated form. The forebrain was involved in five of the nine dogs with disseminated disease, the brainstem in all nine and the cerebellum in one. They had been treated with courses of cytosine arabinoside every three weeks and immunosuppressive doses of prednisolone. Their response to the treatment, in terms of quality of life, was judged by their owners and referring veterinarians to have been excellent in five, good in five and poor in one; their survival times ranged from 78 days to more than 603 days. The cumulative probability of survival at two years was 58.4 per cent. No signs of myelosuppression or other side effects associated with cytosine arabinoside were observed.

Assessment of a pyrogallol red technique for total protein measurement in the cerebrospinal fluid of dogs.

The measurement of protein concentration in the cerebrospinal fluid is a basic analytical method in neurology. In this study, a pyrogallol red technique using a human albumin calibrator previously validated in human medicine was tested for canine samples, and the results were compared with those obtained using urine test strips. Pyrogallol red significantly (P<0.05) but moderately underestimated purified dog albumin and globulins. The imprecision of the technique was low: intra- and between-series coefficients of variation were 1.6 and 4.3 per cent at protein concentrations of about 0.3 g/litre. Over 49 samples, there was good agreement between the pyrogallol red and test strip results (r=0.63), especially for low and high protein concentrations, but misclassifications were observed with '+' test strip readings.

Alpha-tocopherol and probucol reduce autoantibody titer to MDA-LDL in hypercholesterolemic rabbits.

We considered the hypothesis that antioxidant supplementation that increases aortic antioxidant concentrations would reduce autoantibody titer to MDA-LDL, a measure that may indicate in vivo oxidation. We assessed autoantibody titer to MDA-LDL in rabbits before and after 5 months of treatment with a nutritionally adequate hypercholesterolemic diet alone (control) or supplemented with synthetic alpha-tocopherol or probucol. Aortic cholesterol and antioxidants were assessed at the end of treatment. alpha-Tocopherol supplementation increased the ratio of aortic alpha-tocopherol to cholesterol by 20-30-fold, while probucol supplementation increased the ratio of aortic probucol to cholesterol to 4-13 micromol/mol. Before treatment, MDA-LDL autoantibody titer averaged 5.09 +/- 0.24 with no difference among groups (p =.53 by ANOVA). However, after treatment, autoantibody titers differed among groups (p <.03 by ANOVA). Autoantibody titers were similar in rabbits supplemented with alpha-tocopherol and probucol (3.69 +/- 0.21 and 3.73 +/- 0.48, respectively, p = 0.81), and 26% (p <.009) lower in antioxidant supplemented rabbits than unsupplemented hypercholesterolemic rabbits (5.03 +/- 0.47). There was an inverse J relationship between autoantibody titer after treatment and aortic alpha-tocopherol/cholesterol and probucol/cholesterol, with minimum values for autoantibody titers above 8-10 micromol antioxidant/mmol cholesterol. The results of this study are consistent with inhibition of in vivo intra-aortic oxidation when aortic alpha-tocopherol or probucol exceed 8-10 micro;mol/mmol cholesterol.

Low levels of viscous hydrocolloids lower plasma cholesterol in rats primarily by impairing cholesterol absorption.

Hydrocolloids have been proposed as cholesterol-lowering agents, but their viscosity limits their use in human nutrition. A low level (1 %) of hydrocolloids (guar gum, (GG); xanthan gum, (XG); and konjac mannan) was investigated in rats fed 0.2 g/100 g cholesterol diets. Food intake and body weight gain were not altered by the diets. Bile flow and cholesterol bile flux were not modified by diet, whereas the bile acid flux was greater in rats fed hydrocolloid diets. The cecal pool of bile acids was greater than control rats only in rats fed the XG diet (+71%, P<0.001). The fecal excretion of neutral sterols was stimulated in rats fed the hydrocolloid diets; cholesterol apparent digestibility (60% in controls) was reduced to 30-36% in rats fed hydrocolloids. Bile acid fecal excretion was not altered by diet treatment. As a result, apparent steroid balance was about +40 micromol/d in controls and only +10 to +20 micromol/d in rats fed hydrocolloids. Both plasma cholesterol and triglycerides were significantly lower than controls in rats fed XG, but only cholesterol was lower in rats fed the GG diet. These effects were essentially found in the d <1.040 kg/L fraction. Liver cholesterol content was significantly lower than in controls in rats fed the GG or XG diets. Liver HMG CoA reductase was not affected by the hydrocolloid diets. In conclusion, a low percentage of viscous hydrocolloids lowers plasma cholesterol in cholesterol-fed rats. Inhibition of intestinal cholesterol absorption may be the primary mechanism.

Comparative lipid and lipoprotein responses to solid-food diets and defined liquid-formula diets.

BACKGROUND: Liquid-formula diets (LFDs) are useful in metabolic studies of the cholesterolemic effects of dietary lipids because they can be formulated with accuracy, facilitating precise delivery of fatty acids of interest. However, because of differences in composition and nutrient delivery between LFDs and solid-food diets (SFDs), there is a need to determine differences in their effects. OBJECTIVE: Our objective was to compare lipid and lipoprotein responses to changes in total fat, saturated fatty acids (SFAs), and cholesterol in subjects consuming an SFD or LFD. DESIGN: Twenty-one healthy subjects consumed controlled diets representative of an average American diet [AAD; 37% of energy from fat (15% from SFAs), and <50 mg cholesterol/MJ] or a National Cholesterol Education Program (NCEP) Step II diet [26% fat (5% from SFAs) and <25 mg cholesterol/MJ]. Other nutrients were similar between diets. Diets were consumed for 23 d in a randomized, crossover design. RESULTS: For the AAD and NCEP Step II diet, there were no significant differences in lipids and apolipoproteins when the LFD or SFD versions were consumed. In contrast, consumption of the SFD was associated with significantly lower total cholesterol and triacylglycerols than was consumption of the corresponding AAD or Step II LFD (P < 0.05). Subjective ratings of satiety, hunger, and quality of life between diet forms did not differ significantly. CONCLUSIONS: Both LFDs and SFDs yield quantitatively similar cholesterolemic responses to changes in dietary fat, SFAs, and cholesterol. LFDs may offer advantages because they provide easily administered, complete, balanced nutrition without affecting satiety.

A fully automated multicapillary electrophoresis device for DNA analysis.

We describe the construction and performance of a fully automated multicapillary electrophoresis system for the analysis of fluorescently labeled biomolecules. A special detection system allows the simultaneous spectral analysis of all 96 capillaries. The main features are true parallel detection without any moving parts, high robustness, and full compatibility to existing protocols. The device can process up to 40 microtiter plates (96 and 384 well) without human interference, which means up to 15,000 samples before it has to be reloaded.