Assessing Advance Care Planning Fidelity within the Context of Cognitive Impairment: The SHARE Trial.

CONTEXT: Advance care planning (ACP) is critical among primary care patients with cognitive impairment, but few interventions have tested ACP with this population. OBJECTIVE: Describe the development and evaluation of a tool for assessing ACP fidelity within the context of cognitive impairment, including inter-rater reliability, convergent validity, and overall fidelity using clinical trial data. DESIGN: SHARE is a multicomponent intervention inclusive of facilitated ACP conversations. From a two group, single blind, randomized controlled trial, recorded ACP conversations were rated for fidelity. 145 primary care patients and their care partners were randomized to receive the intervention. Participating patients were 80+ years, had a care partner, and indications of cognitive impairment. An ACP Fidelity Checklist was developed with three subscales: Meeting Set-Up; ACP Meeting Topics; and Communication Skills. Scores were converted to percentages (100% = perfect fidelity) with a target of ≥80% fidelity. A post-ACP meeting report completed by ACP facilitators was used to assess convergent validity of the checklist. Intra-class correlation (ICC) was to evaluate inter-rater reliability. RESULTS: ACP conversations averaged 33.6 minutes (SD = 14.1). The mean fidelity score across N = 91 rated meetings was 82.9%, with a range of 77.3%-90.6% for subscales. 63.7% of meetings achieved a rating of ≥80%. Cognitive function was positively associated with patient participation (rho = .59, P < 0.001). For checklist items, ICC scores ranged from 0.43-0.96. Post-ACP meeting form scores were correlated with the checklist Meeting Topics subscale (r = 0.36, P = 0.001). CONCLUSIONS: Assessing the fidelity of ACP conversations involving primary care patients living with cognitive impairment and their care partners is feasible.

Diabetes treatment deintensification in Australians with dementia compared to the general population: A national cohort study.

BACKGROUND: Diagnosis of dementia may change peoples' goals of care. In people with diabetes, this may lead to relaxing treatment targets and reducing the use of diabetes medications. The aim of this study was to examine changes in diabetes medication use before and after initiating medication for dementia. METHODS: A national cohort of people aged 65-97 years, living with dementia and diabetes, and a general population cohort with diabetes matched for age, sex, and index date were extracted from the Australian national medication claims database. Trajectories of diabetes medication use, expressed as mean defined daily dose (DDD) each month for each individual from 24 months before to 24 months after the index date, were estimated using group-based trajectory modeling (GBTM). Cohorts were analyzed separately. RESULTS: People with dementia (N = 1884) and the matched general population (N = 7067) had a median age of 80 years (interquartile range 76-84) and 55% were female. In both models, people exhibited one of five diabetes medication trajectories, with 16.5% of people with dementia and 24.0% of the general population assigned to trajectories that represented deintensification. In the general population model, those on deintensifying trajectories were older than those on stable trajectories (median 83 vs. 79 years). In the dementia cohort model, those on high or low deintensifying trajectories were slightly older (median age 81 or 82, respectively, vs. 80 years) and had at least 1 more comorbidity (median 8 or 7, respectively, vs. 6) than those on stable trajectories. CONCLUSIONS: Initiating medication for dementia does not appear to be a trigger for deintensification of diabetes treatment regimens. Deintensification was more common in the general population; people living with dementia are potentially overtreated for diabetes.

Sharing Health Care Wishes in Primary Care (SHARE) among older adults with possible cognitive impairment in primary care: Study protocol for a randomized controlled trial.

OBJECTIVE: Little is known about effective strategies to improve advance care planning (ACP) for persons with cognitive impairment in primary care, the most common setting of care. We describe a randomized controlled trial to test the efficacy of a multicomponent communication intervention, "Sharing Healthcare Wishes in Primary Care" (SHARE). PARTICIPANTS: Planned enrollment of 248 dyads of adults 80 years and older with possible cognitive impairment and their care partner, from primary care clinics at 2 Mid-Atlantic health systems. METHODS: The treatment protocol encompasses an introductory letter from the clinic; access to a designated facilitator trained in ACP; person-family agenda-setting to align perspectives about the family's role; and print education. The control protocol encompasses minimally enhanced usual care, which includes print education and a blank advance directive. Randomization occurs at the individual dyad-level. Patient and care partner surveys are fielded at baseline, 6-, 12-, and 24- months. Fidelity of interventionist delivery of the protocol is measured through audio-recordings of ACP conversations and post-meeting reports, and by ongoing monitoring and support of interventionists. OUTCOMES: The primary outcome is quality of end-of-life care communication at 6 months; secondary outcomes include ACP process measures. An exploratory aim examines end-of-life care quality and bereaved care partner experiences for patients who die by 24 months. CONCLUSIONS: Caregiver burden, clinician barriers, and impaired decisional capacity amplify the difficulty and importance of ACP discussions in the context of cognitive impairment: this intervention will comprehensively examine communication processes for this special subpopulation in a key setting of primary care. REGISTRATION: ClinicalTrials.gov: NCT04593472.

Fielding the quality of communication questionnaire to persons with cognitive impairment and their family in primary care: A pilot study.

BACKGROUND: The quality of communication (QOC) questionnaire has been widely used to assess foundational aspects of patient-clinician communication about end-of-life (EOL) care. However, this instrument has never before been fielded with primary care patients who have cognitive impairment and their caregivers, a population with unique communication needs. DESIGN: We report on baseline data from a completed pilot study and ongoing efficacy trial of advance care planning involving dyads of primary care patients ages 80 and older with cognitive impairment and their family care partners. Two QOC subscales assessed ratings of general communication and EOL care communication from 0 ("worst") to 10 ("best"). Due to challenges piloting the EOL subscale, we integrated skip logic to improve cognitive accessibility and measurement precision. Participants were first asked whether EOL communication occurred (yes/no); those responding affirmatively were subsequently asked to rate communication. We report experiences with EOL subscale adaptations from our ongoing trial (NCT04593472). RESULTS: Using the original instrument in our pilot (13 dyads), mean patient and family general communication ratings were similar (9.65 and 9.60, respectively), but EOL ratings diverged (4.23 and 5.88, respectively), and "Don't Know" comprised 5% of patient and 32% of family responses. Interviewers reported patient and family participants expressed confusion when asked to rate EOL communication behaviors that had not occurred. Using the adapted instrument in our efficacy trial (43 dyads), EOL communication behaviors were most often reported as not having occurred (76% of patient and 73% of family responses across all items). Mean patient and family EOL subscale ratings were similar (2.23 and 2.26) and responses of "Don't Know" were minimal (<1%). CONCLUSION: The original QOC EOL subscale involves rating conversations that rarely occur in primary care but are important for older adults with cognitive impairment. Subscale adaptations may reduce confusion and response uncertainty and improve measurement accuracy.

Long-Term Survival Outcomes of Patients with Small (≤1 cm) Node-Negative HER2-Positive Breast Cancer Not Treated with Adjuvant Anti-HER2-Targeted Therapy: A 10-Year Follow-Up Study.

Introduction: Human epidermal growth factor receptor 2 (HER2) expression is considered an unfavourable prognostic factor in early breast cancer when the patients are not treated with HER2-targeted therapy. However, the long-term prognostic importance of HER2 expression in small (≤1 cm, stage pT1a-b), node-negative HER2* breast cancer is still incompletely known. Methods: A retrospective analysis was performed based on a prospectively collected database including patients with pT1 breast cancer operated at the Helsinki University Hospital, Finland, between March 2000 and April 2006. In this database, 44 patients with pT1a-bN0M0, HER2* cancer, not treated with adjuvant anti-HER2-targeted therapy (the HER2* group) and 291 pT1a-bN0M0, hormone receptor-positive, HER2-negative cancers (the ER*/HER2- group) were identified and included in the study. Survival outcomes were analysed using the Kaplan-Meier method. Results: The median follow-up time was 9.7 years after primary breast surgery. Ten-year distant disease-free survival (DDFS) was 84.0% in the HER2* group and 98.2% in the ER*/HER2- group (p < 0.001). Ten-year overall survival was only 78.5% in the HER2* group, but 91.7% in the ER*/HER2- group (p = 0.09). Conclusions: Cancer HER2 status is strongly associated with unfavourable DDFS during the first decade of follow-up in patients with small (pT1a-bN0M0) breast cancer when adjuvant anti-HER2-targeted treatment is not administered.

Genetic architecture of tipburn resistance in lettuce.

KEY MESSAGE: Two major QTLs for tipburn were identified in LGs 1 and 5 contributing to resistance in cv. Salinas. The findings suggest pleiotropic effects between leaf crinkliness/savoy and tipburn. Tipburn is a physiological disorder in lettuce that is thought to be caused by a localized deficiency of calcium in leaf tissues. To elucidate the genetic architecture of resistance to tipburn in lettuce, seven recombinant inbred line populations were analyzed in multiple environments and years to identify quantitative trait loci (QTLs) for tipburn. Core height, head firmness, head closure, leaf crinkliness, plant fresh weight, and leaf savoy were also analyzed to investigate whether QTLs for these morphological traits collocated with QTLs for tipburn, which would be indicative of pleiotropic effects. Twenty-three major, intermediate, and minor unique QTLs for tipburn were identified in one or more populations scattered throughout the genome. Two major QTLs for tipburn incidence were identified in linkage groups (LGs) 1 and 5, which determined up to 45 and 66% of the phenotypic variance. The major QTL in LG 1 collocated with the head firmness QTL. The major QTL in LG 5 collocated with the QTL for core height, leaf crinkliness, and head firmness. Further research is needed to determine whether these associations are due to pleiotropic effects of the same gene or if the genes determining these traits are tightly linked. The beneficial alleles at the QTLs in LGs 1 and 5 are present in Lactuca sativa cv. Salinas, the genotype sequenced for the reference genome assembly. Therefore, these QTLs are good targets to identify genes causing tipburn as well as regions for marker-assisted selection to improve resistance to tipburn in lettuce.

Prognostic value of isolated tumour cells in sentinel lymph nodes in early-stage breast cancer: a prospective study.

BACKGROUND: The prognostic significance of isolated tumour cells (ITCs) in the sentinel nodes (SNs) is controversial in early breast cancer, and some centres have abandoned immunohistochemistry to detect ITCs. METHODS: Patients with unilateral pT1N0 breast cancer, operated between February 2001 and August 2005 at a university hospital were included in this prospective, population-based cohort study. Survival of 936 patients with or without isolated tumour cells (ITC) in their SNs were compared with the log-rank test and Cox regression analysis. RESULTS: Eight hundred sixty one (92.0%) patients were ITC-negative (pN0i-) and 75 (8.0%) ITC-positive (pN0i+). Patients with ITC-positive cancer received more frequently adjuvant systemic therapies than those with ITC-negative cancer. The median follow-up time was 9.5 years. Ten-year distant disease-free survival was 95.3% in the pN0i- group and 88.8% in the pN0i+ group (P = 0.013). ITCs were an independent prognostic factor in a Cox regression model (HR = 2.34, 95% CI 1.09-5.04; P = 0.029), together with tumour Ki-67 proliferation index and diameter. ITCs were associated with unfavourable overall survival (P = 0.005) and breast cancer-specific survival (P = 0.001). CONCLUSIONS: We conclude that presence of ITCs in the SNs is an adverse prognostic factor in early small node-negative breast cancer, and may be considered in the decision-making for adjuvant therapy.

Molecular photosensitisers for two-photon photodynamic therapy.

Two-photon excitation has attracted the attention of biologists, especially after the development of two-photon excited microscopy in the nineties. Since then, new applications have rapidly emerged such as the release of biologically active molecules and photodynamic therapy (PDT) using two-photon excitation. PDT, which requires a light-activated drug (photosensitiser), is a clinically approved and minimally invasive treatment for cancer and for non-malignant diseases. This feature article focuses on the engineering of molecular two-photon photosensitisers for PDT, which should bring important benefits to the treatment, increase the treatment penetration depth with near-infrared light excitation, improve the spatial selectivity and reduce the photodamage to healthy tissues. After an overview of the two-photon absorption phenomenon and the methods to evaluate two-photon induced phototoxicity on cell cultures, the different classes of photosensitisers described in the literature are discussed. The two-photon PDT performed with historical one-photon sensitisers are briefly presented, followed by specifically engineered cyclic tetrapyrrole photosensitisers, purely organic photosensitisers and transition metal complexes. Finally, targeted two-photon photosensitisers and theranostic agents that should enhance the selectivity and efficiency of the treatment are discussed.

π-Extended diketopyrrolopyrrole-porphyrin arrays: one- and two-photon photophysical investigations and theoretical studies.

A complete one- and two-photon spectroscopic and photophysical characterization of three diketopyrrolopyrrole (DPP)-porphyrin conjugates is reported. The increased conjugation introduced by the incremental addition of one, two and four DPP units on the meso porphyrin positions strongly affects the optical properties of the systems. Ground and triplet excited state absorption spectra show a gradual broadening and bathochromic shift and a trend to lower energies is also observed for both fluorescence and phosphorescence emission. Interestingly, the fluorescence quantum yield increases along the series, leading to remarkable NIR emission properties for the larger derivatives. Unlike the model porphyrin, all derivatives exhibit high two-photon absorption activity. An increase in two-photon absorption cross-section in the regions 800-840 nm and 910-930 nm is observed moving from one DPP to two DPP appended units, with a value of the order of 4000 GM at 910 nm for the latter system. The four compounds show high efficiency in generating singlet oxygen, with yields ranging from 0.7 to 0.5, envisaging favourable applications in both one- and two-photon photodynamic therapies. A detailed theoretical exploration of both linear (absorption and emission) and non-linear (two-photon absorption) properties proposes an analysis of the experimental spectra and a comprehensive interpretation of the two-photon activity within the series of compounds.

[Myocardial damage and paroxysmal ventricular tachycardia in a dog after Albuterol intoxication]. / Myokardschädigung und Paroxysmale Ventrikuläre Tachykardie bei einem Hund nach Albuterolintoxikation.

Intoxication with the beta2-agonist Albuterol may lead to immediate signs of beta-adrenergic stimulation like excitation, tachypnea and tachycardia. Furthermore, it typically causes severe hypokalemia, which then leads to muscle weakness and which predisposes to ventricular arrhythmias. We describe a dog where albuterol intoxication caused runs of fast paroxysmal ventricular tachycardia that persisted after normalization of the hypokalemia. Based on a markedly elevated serum troponin I level acute myocardial damage was identified as cause of the tachyarrhythmia. Repeated Troponin I measurements and Holter-ECGs were the means to document complete cure.

Symptomatic treatment of ascites with a peritoneo-vesical automated fluid shunt system in a dog.

A six-year-old Rottweiler with chronic ascites and moderate panhypoproteinaemia that had been treated with large volume paracentesis over several months duration was diagnosed with a large bi-atrial mass and hepatic fibrosis. For palliative treatment, a peritoneo-vesical automated fluid shunt system with an integrated chargeable battery and an integrated computer to control pump function and to transmit data transcutaneously was implanted by coeliotomy. The pump was left in place for 10 weeks, eliminating the need for further paracentesis during this time. At the end of this period, no ascites was discernible and serum protein concentrations had returned to their respective reference intervals. As a complication, decubitus with skin perforation had developed above the pump. Besides palliative treatment of chronic refractory ascites, this pump may have application in other conditions characterised by chronic cavity effusion or in peritoneal dialysis.

Response of interleukin-6 during euglycaemic and hyperglycaemic exercise in patients with type 1 diabetes mellitus.

The aim of this randomized, single-blinded cross-over study was to investigate the response of interleukin-6 (IL-6) during moderate aerobic exercise in stable euglycaemia and hyperglycaemia in seven male patients with type 1 diabetes mellitus. IL-6 increased significantly over the entire study period in euglycaemia, but not in hyperglycaemia.

Exercise-induced growth hormone response in euglycaemia and hyperglycaemia in patients with Type 1 diabetes mellitus.

AIMS: To compare exercise-induced growth hormone (GH) response in patients with Type 1 diabetes during stable euglycaemic and hyperglycaemic conditions. METHODS: We conducted a randomized, controlled, single-blinded cross-over trial in seven male patients with well-controlled Type 1 diabetes. The patients cycled twice for 120 min at a level of 55-60% maximal oxygen uptake. Euglycaemia was at 5.0 mmol/l, hyperglycaemia at 11.0 mmol/l. RESULTS: Area under the curve of GH (AUC(GH)) during exercise was significantly higher during euglycaemia [1430 ng ml(-1) min, 95% confidence interval (CI) 703-2910] compared with hyperglycaemia (1061 ng ml(-1) min, 95% CI 538-2091, P = 0.02). CONCLUSIONS: In patients with Type 1 diabetes, GH concentrations during moderate aerobic exercise during stable hyperglycaemic conditions are significantly lower compared with euglycaemia. These findings are compatible with preserved glucose-mediated GH regulation during exercise in individuals with well-controlled Type 1 diabetes.

Use of auscultation and Doppler echocardiography in Boxer puppies to predict development of subaortic or pulmonary stenosis.

BACKGROUND: Boxers are predisposed to subaortic and pulmonic stenosis (SAS, PS). Screening of puppies may be useful in estimating the risk of their developing a defect that potentially compromises life expectancy or exercise tolerance. HYPOTHESIS: Presence of SAS or PS in adult Boxers can be predicted by auscultation and Doppler echocardiography at 9-10 weeks of age. ANIMALS: Eighty-five Boxer puppies examined at 9-10 weeks of age and at 12 months of age. METHODS: Prospective, longitudinal observational study. Auscultation by stethoscope and continuous wave-Doppler echocardiography for peak velocities (V(max)) in the aorta (Ao) and pulmonary artery (PA). RESULTS: Intensity of heart murmurs in puppies correlated with V(max)Ao and V(max)PA in adults. V(max)Ao and V(max)PA in puppies correlated with V(max)Ao and V(max)PA in adults, respectively. From puppy to adult, V(max)Ao increased and V(max)PA remained unchanged. The negative predictive value for absent or only a soft (< or =II/VI) murmur in puppies being associated with V(max)Ao and PA < or = 2.4 m/s as an adult was 90% and < or =3.5 m/s 100%. The negative predictive value of a V(max)< or = 2.4 m/s as a puppy still being < or =2.4 m/s as an adult was 94% for Ao and 96% for PA, and of a V(max)< or = 3.5 m/s, 99% for Ao and 100% for PA. CONCLUSIONS AND CLINICAL IMPORTANCE: Even though V(max)Ao increases during growth in Boxer puppies, indicating relative narrowing of the aorta, puppies with V(max)Ao < or = 2.4 m/s do not usually progress to clinically have relevant SAS at 12 months of age.

Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus--a prospective single-blinded randomised crossover trial.

AIMS/HYPOTHESIS: We assessed systemic and local muscle fuel metabolism during aerobic exercise in patients with type 1 diabetes at euglycaemia and hyperglycaemia with identical insulin levels. METHODS: This was a single-blinded randomised crossover study at a university diabetes unit in Switzerland. We studied seven physically active men with type 1 diabetes (mean +/- SEM age 33.5 +/- 2.4 years, diabetes duration 20.1 +/- 3.6 years, HbA1c 6.7 +/- 0.2% and peak oxygen uptake [VO2peak] 50.3 +/- 4.5 ml min(-1) kg(-1)). Men were studied twice while cycling for 120 min at 55 to 60% of VO2peak, with a blood glucose level randomly set either at 5 or 11 mmol/l and identical insulinaemia. The participants were blinded to the glycaemic level; allocation concealment was by opaque, sealed envelopes. Magnetic resonance spectroscopy was used to quantify intramyocellular glycogen and lipids before and after exercise. Indirect calorimetry and measurement of stable isotopes and counter-regulatory hormones complemented the assessment of local and systemic fuel metabolism. RESULTS: The contribution of lipid oxidation to overall energy metabolism was higher in euglycaemia than in hyperglycaemia (49.4 +/- 4.8 vs 30.6 +/- 4.2%; p < 0.05). Carbohydrate oxidation accounted for 48.2 +/- 4.7 and 66.6 +/- 4.2% of total energy expenditure in euglycaemia and hyperglycaemia, respectively (p < 0.05). The level of intramyocellular glycogen before exercise was higher in hyperglycaemia than in euglycaemia (3.4 +/- 0.3 vs 2.7 +/- 0.2 arbitrary units [AU]; p < 0.05). Absolute glycogen consumption tended to be higher in hyperglycaemia than in euglycaemia (1.3 +/- 0.3 vs 0.9 +/- 0.1 AU). Cortisol and growth hormone increased more strongly in euglycaemia than in hyperglycaemia (levels at the end of exercise 634 +/- 52 vs 501 +/- 32 nmol/l and 15.5 +/- 4.5 vs 7.4 +/- 2.0 ng/ml, respectively; p < 0.05). CONCLUSIONS/INTERPRETATION: Substrate oxidation in type 1 diabetic patients performing aerobic exercise in euglycaemia is similar to that in healthy individuals revealing a shift towards lipid oxidation during exercise. In hyperglycaemia fuel metabolism in these patients is dominated by carbohydrate oxidation. Intramyocellular glycogen was not spared in hyperglycaemia.

Interprofessional pre-qualification clinical education: a systematic review.

A search was made of relevant databases and the reference lists of key textbooks and reviews. Of 420 potentially relevant articles, 25 were included in the review. Medicine, nursing, physiotherapy, occupational therapy and social work were the professions most often included. Aims and activities of interprofessional clinical education (IPCE) programs were varied, and there was inconsistency in outcome evaluation approach and tools. The models of IPCE described in the literature are diverse. The major barriers to IPCE were logistical, and the careful planning and negotiation required to overcome these barriers was time consuming. Detailed planning, stakeholder enthusiasm and commitment appear to be essential to the success of IPCE. The literature provides guiding principles for establishing a program; however, there is limited evidence to support a particular approach.

Experienced physiotherapists as gatekeepers to hospital orthopaedic outpatient care.

OBJECTIVE: To investigate the impact, quality and acceptability of a musculoskeletal screening clinic provided by physiotherapists for patients referred to the outpatient orthopaedic department at a major metropolitan hospital. DESIGN, SETTING AND PARTICIPANTS: Prospective observational trial undertaken between 29 November 2005 and 6 June 2006 at the Northern Hospital (a tertiary teaching hospital in outer Melbourne) of 52 patients with non-urgent musculoskeletal conditions who were assessed by one of two physiotherapists with postgraduate qualifications and subsequently by an orthopaedic surgeon. MAIN OUTCOME MEASURES: Proportion of new patients referred who could have been managed without needing to see a surgeon; level of agreement between physiotherapists and orthopaedic surgeon on diagnoses and management decisions; and levels of satisfaction of patients, referring general practitioners and the orthopaedic surgeon with the physiotherapist-led screening initiative. RESULTS: 45 of 52 selected patients (31 women and 21 men; mean age, 53.3 years) attended their appointment with the physiotherapist; of these, 38 also attended a later appointment with the orthopaedic surgeon. Seven of the 38 patients were listed for surgery, and seven others needed management by the surgeon (injection for three, imaging for four). Almost two-thirds (63%) were appropriate for non-surgical management. The physiotherapists identified the same patient management plans as the surgeon for 74% of the group. Patients and doctors reported high levels of satisfaction with the physiotherapist-led service. CONCLUSIONS: Nearly two-thirds of patients with non-urgent musculoskeletal conditions referred by their GPs to one public outpatient orthopaedic department did not need to see a surgeon at the time of referral, and were appropriately assessed and managed by experienced, qualified physiotherapists.

[Simultaneous defect of visual fields and loss of libido--a coincidence?]. / Gleichzeitiger Gesichtsfelddefekt und Libidoverlust - Zufall?

We present the case of a 60 year old male patient with incidentally detected visual abnormalities. Detailed personal history revealed a hypogonadism that had been present for several years. Further investigations established the diagnosis of an infiltrative macroadenoma. Medical treatment with cabergoline led to a rapid regression of ophthalmologic symptoms and, subsequently, of tumor size. In male subjects symptoms of hypogonadism are often reported only late in the course of the disease, thereby leading to a generally larger tumor size at the point of diagnosis. In contrast to other pituitary tumors that are mainly treated by surgery, medical treatment with dopamine agonists is the principal therapeutic option in prolactinomas.