"It Took the Stress out of Getting Help": The STAR-C-Telemedicine Mixed Methods Pilot.

BACKGROUND: Caring for a family member with Alzheimer's disease and related dementias can be mentally and physically taxing. Support programs are available to mitigate the strain of care, but caregivers report access challenges (e.g., distance). STAR-C is an evidence-based, effective, one-on-one caregiver educational intervention. However, family caregivers who do not live near a STAR-C consultant (e.g., rural caregivers) cannot participate in the program. The earth-bound mode presents a critical barrier to widely-available caregiver support. OBJECTIVES: We assessed the feasibility, preliminary efficacy, and cost of implementing a caregiver support intervention (STAR-C-Telemedicine), using Internet-based videoconferencing. DESIGN: Using a mixed-methods approach, we examined feasibility and pre- and post-intervention changes in caregiver burden. Focus groups provided feedback on program acceptability. SETTING: Participants, in their own homes, connected the university-based study staff using videoconferencing technology. PARTICIPANTS: Twenty family caregivers for those with dementia consented to the study. INTERVENTION: The STAR-C-TM intervention included 8 weekly sessions in which the universitybased consultant met (via videoconferencing) with caregivers in their homes. The intervention focused on identifying upsetting behaviors and identifying triggers to the behaviors. MEASUREMENTS: We assessed caregiver burden, depression and desire to institutionalize prior to and after the intervention. RESULTS: Fourteen caregivers (82% of those who started the intervention) completed all study components. We found statistically significant reductions in caregiver burden. Caregivers liked the videoconferencing option. Almost two-thirds reported, given the choice, that they would prefer it over an in-person offering. STAR-C-TM saved, on average, $1150/per caregiver over the traditional program. Qualitative findings supported the quantitative data. CONCLUSIONS: Telemedicine-based support for family caregivers is a feasible and cost-effective option. As the prevalence of dementia grows, programs such as STAR-C-TM can fill an important gap in caregiver education and support.

Population Pharmacokinetic/Pharmacodynamic Modeling of Tumor Size Dynamics in Pembrolizumab-Treated Advanced Melanoma.

Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.

Using Model-Based "Learn and Confirm" to Reveal the Pharmacokinetics-Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE-001 Trial.

Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at <0.3 mg/kg every 3 weeks, but linear in the clinical dose range. Saturation of ex vivo target engagement in blood began at ≥1 mg/kg every 3 weeks, and a steady-state dose of 2 mg/kg every 3 weeks was needed to reach 95% target engagement, supporting examination of 2 mg/kg every 3 weeks in ongoing trials in melanoma and other advanced cancers.

Translational Pharmacokinetic/Pharmacodynamic Modeling of Tumor Growth Inhibition Supports Dose-Range Selection of the Anti-PD-1 Antibody Pembrolizumab.

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition. Human simulations were performed using clinical pharmacokinetic data, literature values, and in vitro parameters for drug distribution and binding. Biological and mathematical uncertainties were included in simulations to generate expectations for dose response. The results demonstrated a minimal increase in efficacy for doses higher than 2 mg/kg. The findings of the translational model were successfully applied to select 2 mg/kg as the lowest dose for dose-ranging evaluations.

Pre-death grief in Parkinson's caregivers: a pilot survey-based study.

OBJECTIVE: To evaluate the evidence for pre-death grief in caregivers (CGs) of persons with Parkinson's disease (PD) and to compare non-motor PD symptoms (cognitive decline, depression, hallucinations) versus motor symptoms (fluctuations of mobility) for associations with CG grief reactions. BACKGROUND: Prolonged grief in response to loss has been associated with negative outcomes and decreased well-being in caregivers (i.e. spouse or adult child) of relatives with dementia. In Parkinson's disease (PD) the negative impact of providing care has been referred to as caregiver strain. Grief has not been explored in PD caregivers, and understanding grief may offer new insights for future intervention. METHODS: Volunteer caregivers (n = 74) filled out the Marwit and Meuser Caregiver Grief Inventory (MM-CGI-SF) which measures 3 types (i.e. subscales) of grief: Personal Sacrifice and Burden, Heartfelt Sadness and Longing, Worry and Felt Isolation. This scale also provided a total grief score. Volunteer caregivers also responded to self-reported UPDRS questions about the motor and non-motor symptoms of their PD relative (i.e. spouse or parent). T-tests were used to correlate CG subscales of grief with patient variables. A hierarchical regression analysis was used to determine the predictive contribution of motor and nonmotor symptoms to grief. RESULTS: Grief based on the total score was found in 17% of CGs. Grief was significantly higher in CG's whose relative had more severe symptoms. The type of grief experienced was similar across all three subscales. Hierarchical regression analysis revealed that nonmotor symptoms explained slightly more of the variance (14-23%) than motor symptoms (11-17%). CONCLUSIONS: This study revealed that pre-death grief is a significant finding in PD caregivers. The severity of symptoms and the presence of nonmotor symptoms, especially cognitive decline, predict caregivers who are at greatest risk of prolonged grief; however it should be kept in mind that motor symptoms also contribute.

Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers.

A pharmacokinetic/pharmacodynamic (PK/PD) study of the tyrosine kinase inhibitor sunitinib was conducted in 12 healthy volunteers using blood pressure and circulating biomarker levels as PD markers. Blood pressure was measured, and plasma concentration-time courses of sunitinib, its major metabolite SU12662, vascular endothelial growth factors VEGF-A and VEGF-C, and soluble VEGF receptor-2 (sVEGFR-2) were studied in healthy subjects receiving 50 mg of sunitinib orally for 3-5 consecutive days. Using NONMEM, PK/PD models were established that predicted changes (expressed as multiples relative to baseline values) in systolic blood pressure, diastolic blood pressure, VEGF-A level, and sVEGFR-2 level, of 1.10, 1.18, 2.24, and 0.76, respectively, for a typical subject after 4 weeks of treatment with 50 mg/day. Simulated blood pressure-time courses compare excellently with published data in patients, whereas changes in circulating biomarkers were greater in patients than simulations suggest for healthy subjects. In conclusion, the tumor-independent pharmacological response to sunitinib could be described by PK/PD models, thereby facilitating model-based investigations with antiangiogenic drugs, using blood pressure and circulating proteins as biomarkers.

Bartonella infections and HIV disease.

Successful assessment and treatment of Bartonella in HIV-seropositive people depends on nursing's fundamental role in the management of these bacterial infections. Bartonella species are responsible for a variety of infections, including cat scratch disease and bacillary angiomatosis, which can be debilitating to people living with AIDS. This paper provides an overview of the clinical presentation and nursing management of Bartonella infection in PLWAs. The author discusses common diagnostic procedures, treatment strategies, and the nurse's role in caring for patients with a Bartonella infection.

The organization structure and regulatory elements of Chlamydomonas histone genes reveal features linking plant and animal genes.

The genome of the green alga Chlamydomonas reinhardtii contains approximately 15 gene clusters of the nucleosomal (or core) histone H2A, H2B, H3 and H4 genes and at least one histone H1 gene. Seven non-allelic histone gene loci were isolated from a genomic library, physically mapped, and the nucleotide sequences of three isotypes of each core histone gene species and one linked H1 gene determined. The core histone genes are organized in clusters of H2A-H2B and H3-H4 pairs, in which each gene pair shows outwardly divergent transcription from a short (< 300 bp) intercistronic region. These intercistronic regions contain typically conserved promoter elements, namely a TATA-box and the three motifs TGGCCAG-G(G/C)-CGAG, CGTTGACC and CGGTTG. Different from the genes of higher plants, but like those of animals and the related alga Volvox, the 3' untranslated regions contain no poly A signal, but a palindromic sequence (3' palindrome) essential for mRNA processing is present. One single H1 gene was found in close linkage to a H2A-H2B pair. The H1 upstream region contains the octameric promoter element GGTTGACC (also found upstream of the core histone genes) and two specific sequence motifs that are shared only with the Volvox H1 promoters. This suggests differential transcription of the H1 and the core histone genes. The H1 gene is interrupted by two introns. Unlike Volvox H3 genes, the three sequenced H3 isoforms are intron-free. Primer-directed PCR of genomic DNA demonstrated, however, that at least 8 of the about 15 H3 genes do contain one intron at a conserved position. In synchronized C. reinhardtii cells, H4 mRNA levels (representative of all core histone mRNAs) peak during cell division, suggesting strict replication-dependent gene control. The derived peptide sequences place C. reinhardtii core histones closer to plants than to animals, except that the H2A histones are more animal-like. The peptide sequence of histone H1 is closely related to the V. carteri VH1-II (66% identity). Organization of the core histone gene in pairs, and non-polyadenylation of mRNAs are features shared with animals, whereas peptide sequences and enhancer elements are shared with higher plants, assigning the volvocalean histone genes a position intermediate between animals and plants.

Two histone H1-encoding genes of the green alga Volvox carteri with features intermediate between plant and animal genes.

Southern hybridization indicated the presence of at least two and possibly four histone H1-encoding genes occurring as singlets in the Volvox carteri genome. Two of these genes, H1-I and H1-II, have been cloned and characterized. Their coding sequences are each interrupted by three introns, but only the position of the second intron is identically conserved in both H1-I and H1-II. The encoded 260-amino-acid (aa) (H1-I) and 240-aa (H1-II) polypeptides possess the typical tripartite organization of animal H1 histones, with variable N- and C-terminal domains flanking a conserved 'globular' DNA-binding domain. Extensive differences in their variable regions suggest that H1-I and H1-II (62% identity) represent two isotypes with different functions. A prominent KAPKAP-KAA motif in the H1-I N-terminal region, similarly seen in single H1 variants of a mosquito and a nematode, has a putative function in packing condensed subtypes of chromatin. Different from higher plants, but like animals, the H1 genes of V. carteri possess a typical 3' palindrome for mRNA processing, resulting in non-polyadenylated mRNAs. Transcription initiates 33 nucleotides (nt) (H1-I) and 26 nt (H1-II) downstream of typical TATA boxes. A putative 20-bp conserved enhancer element upstream of each TATA box closely resembles the consensus sequence associated with the nucleosomal histone-encoding genes in V. carteri [Müller et al., Gene 93 (1990) 167-175] and suggests stringent regulation. Accordingly, transcription of H1 was shown to be restricted to late embryogenesis, when new flagella are produced. We discuss the inferred accessory role of histone H1 proteins in stabilizing axonemal microtubules, as has been recently observed in sea urchin flagella [Multigner et al., Nature 360 (1992) 33-39].

Reverse transcriptase families and a copia-like retrotransposon, Osser, in the green alga Volvox carteri.

By using the polymerase chain reaction (PCR) we have isolated and sequenced two distinct families of reverse transcriptase (RT) sequences from the genome of the colonial alga, Volvox carteri. Probing a genomic library with these RT clones revealed copia-like retrotransposons. One of these elements, named Osser, is 4,875 bp long, bordered by 197-bp identical long terminal repeats (LTRs), and shows the typical organization of retrotransposons belonging to the copia-Tyl group. This is the first complete copia-like retrotransposon sequence described in a green alga.

Hemodynamic responses to upright exercise of adolescent cardiac transplant recipients.

To characterize the hemodynamic response to exercise after cardiac transplantation, we asked seven adolescent transplant patients (aged 15.1 +/- 0.7 years; mean +/- SE) to perform upright discontinuous exercise to volitional exhaustion on a mechanically braked cycle ergometer. Data were compared with those of seven control subjects matched for age, gender, body mass, percentage of fat, and body surface area. The transplant group had lower peak power output values (92 +/- 13 vs 146 +/- 30 watts; p less than or equal to 0.001) and maximum oxygen consumption values (22 +/- 8 vs 32 +/- 8 ml/kg per minute; p less than or equal to 0.03), despite achieving the same peak venous lactic acid concentration (6.2 +/- 3 vs 5.9 +/- 3 mEq/L; p = not significant). The transplant group had a diminished heart rate in response to exercise--44% lower than the control group had (delta = 49 +/- 6.4 vs 87 +/- 9.1 beats/min; p = 0.005). The cardiac output response to exercise was maintained in the transplant group (delta = 6.5 +/- 1.5 vs 4.6 +/- 0.8 L/min; p = not significant) by an augmented stroke volume response (delta = 31 +/- 10 vs -4 +/- 3.4 ml; p = 0.01), which may relate to a greater decrease in systemic vascular resistance during exercise (delta = -13.7 +/- 2.2 vs -6.3 +/- 1.2 Wood units; p = 0.02). Thus adolescents who have undergone cardiac transplantation have a normal cardiac output response to upright exercise. This is accomplished, despite a blunted heart rate response, by an augmented stroke volume that may relate to the greater decrease in systemic resistance during exercise.

Rapid progression of aortic aneurysms after patch aortoplasty repair of coarctation of the aorta.

OBJECTIVES: This study was undertaken to evaluate the progression of aortic aneurysms after patch aortoplasty repair of coarctation of the aorta. BACKGROUND: Previous studies demonstrated a 5% to 25% incidence rate of repair site aneurysm 3 to 18 years after patch aortoplasty repair of coarctation. The natural history of aneurysmal progression in this disease entity has not previously been examined. METHODS: Twenty-nine patients were identified 5.6 +/- 1 years (mean +/- SE) postoperatively and classified into two groups: Group A, aneurysm (n = 7); Group B, no aneurysm (n = 22). The presence of an aneurysm was defined angiographically as a ratio of the repair site diameter to diaphragmatic aortic diameter (aortic ratio) greater than or equal to 1.5. A 23% prevalence (7 of 29) of aortic aneurysm was identified. One patient in Group A underwent semiemergency aneurysmectomy and two patients in Group B were lost to follow-up. The remaining 26 patients were reevaluated 3 to 5 years later by clinical examination and chest radiography. Aortograms were performed in all patients with suspected aneurysm formation or progression. RESULTS: Five of six patients in Group a demonstrated progressive aneurysmal dilation documented by an increase in aortic ratio from 1.64 +/- 0.06 to 2.04 +/- 0.2 (p = 0.03) and an increase in absolute aneurysm diameter from 2.5 +/- 0.3 to 3.6 +/- 0.5 cm (p = 0.006). Only 1 of 20 patients in Group B had evidence of new aneurysmal dilation (p less than 0.05 vs. Group A). Four patients in Group A have undergone elective aneurysmectomy, with equal distribution of true and pseudoaneurysms by pathologic examination. CONCLUSIONS: Aortic aneurysm formation is common after patch aortoplasty repair of coarctation of the aorta. The majority of patients with an aortic ratio greater than or equal to 1.5 will show significant progressive aneurysmal dilation within 3 to 5 years.

Intermediate-term outcome after pulmonary balloon valvuloplasty: comparison with a matched surgical control group.

To assess late (4 to 5 years) gradient reduction after pulmonary balloon valvuloplasty in childhood, and to compare the effectiveness of valvuloplasty with that of surgical valvotomy, 20 valvuloplasty-treated children and their age- and gradient-matched surgical control patients underwent prospective, noninvasive evaluation. The average age at intervention was 4.3 +/- 1 years for the valvuloplasty group versus 4.7 +/- 0.8 years for the surgical control group (p = NS). Before intervention the peak systolic pulmonary stenosis gradient was 76 +/- 5 and 74 +/- 4.4 mm Hg for the valvuloplasty and surgery groups, respectively (p = NS). Late evaluation consisted of clinical examination, two-dimensional echocardiogram and Doppler study, 24-hour Holter monitoring, 12-lead electrocardiogram, exercise treadmill study and chest radiograph performed an average of 5.3 +/- 0.3 years after valvuloplasty and 11.7 +/- 0.5 years after surgery (p less than 0.01). The patients treated with balloon valvuloplasty had no evidence of restenosis; the residual pulmonary stenosis gradient at follow-up was 24 +/- 2.7 mm Hg (range 8 to 48) versus 35 +/- 3.6 mm Hg (range 19 to 70) immediately after valvuloplasty (p = NS). Comparison of the late residual gradients between treatment groups showed no hemodynamically significant difference (24 +/- 2.7 versus 16 +/- 1.5 mm Hg, balloon versus surgery; p less than 0.01). However, there was, a significant difference in the degree and severity of pulmonary valve insufficiency and ventricular ectopic activity between groups. In the balloon valvuloplasty group 11 patients had no pulmonary insufficiency, and the remaining 9 had mild insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Organization and transcription of Volvox histone-encoding genes: similarities between algal and animal genes.

The nucleotide sequences of two non-allelic histone H2A-H2B gene loci of the green alga Volvox carteri have been determined. Each locus contains a divergently arranged H2A-H2B gene pair. The encoded proteins differ in one (H2A) and 16 positions (H2B), respectively. The coding regions are separated by short intercistronic segments (256 bp and 298 bp) containing TATA boxes and a central tandem repeat of a conserved 20-bp element as the putative histone-specific transcription signals. The 3'-untranslated regions exhibit a characteristic 3'-palindrome and weakly conserved spacer elements. Transcription in one gene locus was shown to initiate 48 bp upstream from H2A and 59 bp upstream from H2B. Contrary to higher plants, V. carteri histone mRNAs are nonpolyadenylated. S1 mapping and Northern-blotting experiments indicated that V. carteri histone mRNAs are terminated at the 3'-palindrome by the same mechanism that operates in vertebrates and sea urchins.