Development of a complex community pharmacy intervention package using theory-based behaviour change techniques to improve older adults' medication adherence.

BACKGROUND: To improve the effectiveness of interventions targeting non-adherence in older adults, a systematic approach to intervention design is required. The content of complex interventions and design decisions are often poorly described in published reports which makes it difficult to explore why they are ineffective. This intervention development study reports on the design of a community pharmacy-based adherence intervention using 11 Behaviour Change Techniques (BCTs) which were identified from previous qualitative research with older patients using the Theoretical Domains Framework. METHODS: Using a group consensus approach, a five-step design process was employed. This focused on decisions regarding: (1) the overall delivery format, (2) formats for delivering each BCT; (3) methods for tailoring BCTs to individual patients; (4) intervention structure; and (5) materials to support intervention delivery. The APEASE (Affordability; Practicability; Effectiveness/cost-effectiveness; Acceptability; Side effects/safety; Equity) criteria guided the selection of BCT delivery formats. RESULTS: Formats for delivering the 11 BCTs were agreed upon, for example, a paper medicines diary was selected to deliver the BCT 'Self-monitoring of behaviour'. To help tailor the intervention, BCTs were categorised into 'Core' and 'Optional' BCTs. For example, 'Feedback on behaviour' and 'Action planning' were selected as 'Core' BCTs (delivered to all patients), whereas 'Prompts and cues' and 'Health consequences' were selected as 'Optional' BCTs. A paper-based adherence assessment tool was designed to guide intervention tailoring by mapping from identified adherence problems to BCTs. The intervention was designed for delivery over three appointments in the pharmacy including an adherence assessment at Appointment 1 and BCT delivery at Appointments 2 and 3. CONCLUSIONS: This paper details key decision-making processes involved in moving from a list of BCTs through to a complex intervention package which aims to improve older patients' medication adherence. A novel approach to tailoring the content of a complex adherence intervention using 'Core' and 'Optional' BCT categories is also presented. The intervention is now ready for testing in a feasibility study with community pharmacists and patients to refine the content. It is hoped that this detailed report of the intervention content/design process will allow others to better interpret the future findings of this work.

A non-randomised pilot study of the Solutions for Medication Adherence Problems (S-MAP) intervention in community pharmacies to support older adults adhere to multiple medications.

BACKGROUND: Older patients prescribed multiple medications commonly experience difficulties with adherence. High-quality evidence on interventions targeting older patients is lacking. Theory is rarely used to tailor adherence solutions. This study aimed to pilot test a novel intervention, developed using the Theoretical Domains Framework, which guides community pharmacists in identifying adherence barriers and delivering tailored solutions (behaviour change techniques). Key study procedures (e.g. recruitment, data collection) for a future randomised controlled trial (cRCT) were also assessed. METHODS: Using purposive sampling, this non-randomised pilot study aimed to recruit 12 community pharmacies (six in Northern Ireland; six in London, England). Pharmacists were trained to deliver the intervention to non-adherent older patients (maximum 10 per pharmacy; target n = 60-120) aged ≥ 65 years (reduced to 50 years due to recruitment challenges) and prescribed ≥ 4 regular medicines. The intervention, guided by an iPad web-application, was delivered over 3-4 face-to-face or telephone sessions, tailored to specific barriers to adherence. We assessed the feasibility of collecting adherence data (primary outcome: self-report and dispensing records), health-related quality of life (HRQOL) and unplanned hospitalisations (secondary outcomes) at baseline and 6-months. The final decision on progressing to a cRCT, using pre-defined 'stop-amend-go' criteria, is presented. RESULTS: Fifteen pharmacists from 12 pharmacies were recruited and trained. One pharmacy subsequently dropped out. Sixty patients were recruited (meeting the 'Amend' progression criteria), with 56 receiving the intervention. Adherence barriers were identified for 55 patients (98%) and a wide range of behaviour change solutions delivered (median: 5 per patient). Self-report and dispensing adherence data were available for 37 (61.7%) and 44 (73.3%) patients, respectively. HRQOL data were available for 35 (58.3%) patients. GP-reported and self-reported hospitalisations data were available for 47 (78.3%) and 23 (38.3%) patients, respectively. All progression concepts were met (nine 'Go' and three 'Amend' criteria). CONCLUSION: This study demonstrates the feasibility of key study procedures (e.g. pharmacy recruitment) and delivery of a tailored adherence intervention in community pharmacies. However, modifications are required to enhance issues identified with patient recruitment, retention and missing data. A future definitive cRCT will explore the effectiveness of the intervention. TRIAL REGISTRATION: ISRCTN, ISRCTN73831533 , Registered 12 January 2018.

Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel.

Voltage-sensitive sodium channels are responsible for the initiation and propagation of the action potential and therefore are important for neuronal excitability. Complementary DNA clones encoding the beta 1 subunit of the rat brain sodium channel were isolated by a combination of polymerase chain reaction and library screening techniques. The deduced primary structure indicates that the beta 1 subunit is a 22,851-dalton protein that contains a single putative transmembrane domain and four potential extracellular N-linked glycosylation sites, consistent with biochemical data. Northern blot analysis reveals a 1,400-nucleotide messenger RNA in rat brain, heart, skeletal muscle, and spinal cord. Coexpression of beta 1 subunits with alpha subunits increases the size of the peak sodium current, accelerates its inactivation, and shifts the voltage dependence of inactivation to more negative membrane potentials. These results indicate that the beta 1 subunit is crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the rat brain sodium channel.

A pilot study of the S-MAP (Solutions for Medications Adherence Problems) intervention for older adults prescribed polypharmacy in primary care: study protocol.

BACKGROUND: Adhering to multiple medications as prescribed is challenging for older patients (aged ≥ 65 years) and a difficult behaviour to improve. Previous interventions designed to address this have been largely complex in nature but have shown limited effectiveness and have rarely used theory in their design. It has been recognised that theory ('a systematic way of understanding events or situations') can guide intervention development and help researchers better understand how complex adherence interventions work. This pilot study aims to test a novel community pharmacy-based intervention that has been systematically developed using the Theoretical Domains Framework (12-domain version) of behaviour change. METHODS: As part of a non-randomised pilot study, pharmacists in 12 community pharmacies across Northern Ireland (n = 6) and London, England (n = 6), will be trained to deliver the intervention to older patients who are prescribed ≥ 4 regular medicines and are non-adherent (self-reported). Ten patients will be recruited per pharmacy (n = 120) and offered up to four tailored one-to-one sessions, in the pharmacy or via telephone depending on their adherence, over a 3-4-month period. Guided by an electronic application (app) on iPads, the intervention content will be tailored to each patient's underlying reasons for non-adherence and mapped to the most appropriate solutions using established behaviour change techniques. This study will assess the feasibility of collecting data on the primary outcome of medication adherence (self-report and dispensing data) and secondary outcomes (health-related quality of life and unplanned hospitalisations). An embedded process evaluation will assess training fidelity for pharmacy staff, intervention fidelity, acceptability to patients and pharmacists and the intervention's mechanism of action. Process evaluation data will include audio-recordings of training workshops, intervention sessions, feedback interviews and patient surveys. Analysis will be largely descriptive. DISCUSSION: Using pre-defined progression criteria, the findings from this pilot study will guide the decision whether to proceed to a cluster randomised controlled trial to test the effectiveness of the S-MAP intervention in comparison to usual care in community pharmacies. The study will also explore how the intervention components may work to bring about change in older patients' adherence behaviour and guide further refinement of the intervention and study procedures. TRIAL REGISTRATION: This study is registered at ISRCTN: 10.1186/ISRCTN73831533.

A voltage-dependent gating transition induces use-dependent block by tetrodotoxin of rat IIA sodium channels expressed in Xenopus oocytes.

We have utilized molecular biological techniques to demonstrate that rat IIA sodium channels expressed in Xenopus oocytes were blocked by tetrodotoxin (TTX) in a use-dependent manner. This use dependence was the result of an increased affinity of the channels for TTX upon depolarization, most likely due to a conformational change in the channel. Using a mutant with a slower macroscopic rate of inactivation, we have demonstrated that this conformational change is not the transition into the fast-inactivated state. The transition is probably one occurring during activation of the channel, as suggested by the fact that one sodium channel mutant demonstrated comparable depolarizing shifts in the voltage dependence of both activation and use-dependent block by TTX. The transition occurred at potentials more negative than those resulting in channel conductance, suggesting that the conformational change that causes use-dependent block by TTX is a closed-state voltage-dependent gating transition.

RNA editing generates a diverse array of transcripts encoding squid Kv2 K+ channels with altered functional properties.

We have cloned a Kv2 potassium channel from squid optic lobe termed sqKv2. Multiple overlapping sqKv2 cDNA clones differed from one another at specific positions by purine transitions. To test whether the purine transitions were generated by RNA editing, we compared a 360 nucleotide genomic sequence with corresponding cDNA sequences (encoding S4-S6) isolated from individual animals and lying on a single gene and exon. cDNA sequences differed from genomic sequence at 17 positions, resulting in 28 unique sequences. There was invariantly an adenosine in the genomic sequence and a guanosine in the edited cDNA sequences. Two of the edits altered the rates of channel closure and slow inactivation. These results extend selective RNA editing to invertebrate taxa and represents a novel mechanism for the posttranscriptional modulation of voltage-gated ion channels.

A peptide segment critical for sodium channel inactivation functions as an inactivation gate in a potassium channel.

The short cytoplasmic peptide segment connecting domains III and IV of voltage-gated sodium channels (III-IV linker) is essential for fast inactivation. To test the functional similarity between the III-IV linker and the potassium channel inactivation particle, we attached the III-IV linker to the amino terminus of a noninactivating potassium channel. This chimeric channel inactivated rapidly and displayed biophysical properties similar to Shaker A-type potassium channels. Recovery from inactivation in the chimeric channels was accelerated by high external potassium, consistent with the idea that potassium ions passing through the channel displaced the III-IV linker inactivation particle. A mutation that completely abolishes fast inactivation in rat brain sodium channels also completely abolished inactivation in the chimera. These results demonstrate that the sodium channel III-IV linker can function as a fast inactivation gate and suggest a functional relationship between the fast inactivation processes of sodium and potassium channels.

Maternal, uteroplacental, and fetoplacental hemodynamic and Doppler velocimetric changes during epidural anesthesia in normal labor.

Pulsed Doppler and M-mode maternal echocardiography were combined with uterine and umbilical artery Doppler velocimetry to characterize the hemodynamic changes associated with fluid preload and epidural anesthesia in 12 normal laboring gravidas at term. Fluid preload alone was associated with significant (P less than .05) increases in heart rate (11%), stroke volume (10%), and cardiac output (20%), and a decrease in systemic vascular resistance (19%). There were no changes in mean arterial pressure (MAP) or ejection fraction during any stage of the study. Following placement of the epidural block, stroke volume and cardiac output returned to values not significantly different from baseline, whereas heart rate remained elevated and systemic vascular resistance remained decreased. There were no changes in uterine or umbilical artery systolic-diastolic (S-D) ratios during any stage of the study. We conclude that fluid preload and epidural anesthesia cause significant changes in maternal cardiac output, heart rate, stroke volume, and systemic vascular resistance without affecting MAP. These maternal changes do not correlate with any changes in uterine or umbilical artery S-D ratios following epidural anesthesia in the normal laboring gravida.

Intravenous pancuronium bromide for fetal neuromuscular blockade during intrauterine transfusion for red-cell alloimmunization.

Intravenous pancuronium bromide was administered into the umbilical cord by funipuncture to effect temporary fetal paralysis. Neuromuscular blockade was achieved in 12 fetuses undergoing a total of 34 intrauterine procedures for the treatment of severe red-cell alloimmunization. The same initial dose of 0.2 mg/kg fetal weight estimated by ultrasound was used in all cases, but anemic fetuses did not resume movement for prolonged periods. A relationship among fetal hematocrit, adjusted dose, and duration of paralysis was described by the equation: Duration (hours) = 5.24 + 10.30 adjusted dose (mg/kg) - 0.16 hematocrit (%) (R2 = 0.49; P less than .001). Intravenous pancuronium was found to be a safe and effective method for cessation of fetal movement during intrauterine procedures.

Cyanotic maternal heart disease in pregnancy.

Cyanotic heart disease has major implications for maternal and fetal well-being during pregnancy. This article reports six patients with cyanotic congenital heart disease recently managed at our institutions. Although the maternal condition deteriorated to some extent during each pregnancy, it was the fetal condition that ultimately dictated delivery in each case.

Legal aspects of pesticides and toxic substances testing requirements.

The United States Environmental Protection Agency administers several laws and programs through which it reviews the hazard potential of pesticides and other toxic substances which may present a risk to human health or the environment. The Agency's ability to assess hazard as required by law depends in part on test data developed through testing standards in Agency regulations. In reviewing the Agency's actions in this regard, the courts emphasize the importance of reasoned regulatory decisions. The legal requirements to assess risk and provide and provide reasoned decisions in this regard establish the legal importance of testing guidelines and test data, and indicate that sound test methodology is as important legally as it is scientifically.

Misdiagnosis of a normal fetal platelet count after coagulation of intrapartum scalp samples in autoimmune thrombocytopenic purpura.

Intrapartum fetal scalp sampling for platelet counts in maternal autoimmune thrombocytopenia has been advocated for determining route of delivery. We report a case in which two coagulated scalp samples were believed to indicate a normal fetal platelet count. As a result, vaginal delivery of a severely thrombocytopenic fetus was allowed.

Discrimination of heterogenous mRNAs encoding strychnine-sensitive glycine receptors in Xenopus oocytes by antisense oligonucleotides.

Three synthetic oligodeoxynucleotides complementary to different parts of an RNA encoding a glycine receptor subunit were used to discriminate heterogenous mRNAs coding for glycine receptors in adult and neonatal rat spinal cord. Injection of the three antisense oligonucleotides into Xenopus oocytes specifically inhibited the expression of glycine receptors by adult spinal cord mRNA. In contrast, the antisense oligonucleotides were much less potent in inhibiting the expression of glycine receptors encoded by neonatal spinal cord mRNA. Northern blot analysis revealed that the oligonucleotides hybridized mostly to an adult cord transcript of approximately 10 kilobases in size. This band was also present in neonatal spinal cord mRNA but its density was about one-fourth of the adult cord message. There was no intense band in the low molecular weight position (approximately 2 kilobases), the existence of which was expected from electrophysiological studies with size-fractionated mRNA of neonatal spinal cord. Our results suggest that in the rat spinal cord there are at least three different types of mRNAs encoding functional strychnine-sensitive glycine receptors.

The adult rat brain beta 1 subunit modifies activation and inactivation gating of multiple sodium channel alpha subunits.

The sodium channel from adult rat brain consists of a high molecular weight alpha subunit associated with low molecular weight subunits termed beta 1 and beta 2. Coexpression of beta 1 accelerates the macroscopic kinetics of inactivation of adult rat brain IIA, embryonic rat brain III, and rat skeletal muscle SkM1 sodium channel alpha subunits. In addition, beta 1 accelerates the kinetics of activation, as observed with a non-inactivating rat brain IIA mutant. Analysis of the effects of beta 1 on the slowly inactivating brain III alpha subunit shows that both of these effects may be the result of changes in the modal gating behavior of the sodium channels expressed in Xenopus oocytes. Although the adult rat brain beta 1 subunit modulates the functional properties of rat skeletal muscle and embryonic brain III sodium channel alpha subunits, mRNA hybridizing to a beta 1 subunit cDNA probe was only faintly detected in RNA from adult skeletal muscle and not at all in RNA from embryonic brains. These results indicate that the adult rat brain beta 1 subunit can modify the modal gating properties of sodium channel alpha subunits with which it is not normally associated, suggesting the presence of conserved domains for interactions between the different alpha and beta 1 subunits of the sodium channel.

Amino acid residues required for fast Na(+)-channel inactivation: charge neutralizations and deletions in the III-IV linker.

The cytoplasmic linker connecting domains III and IV of the voltage-gated Na+ channel is thought to be involved in fast inactivation. This linker is highly conserved among the various Na+ channels that have been cloned. In the rat brain IIA Na+ channel, it consists of 53 amino acids of which 15 are charged. To investigate the role of this linker in inactivation, we mutated all 15 of the charged residues in various combinations. All but one of these mutants expressed functional channels, and all of these inactivated with kinetics similar to the wild-type channel. We then constructed a series of deletion mutations that span the III-IV linker to determine if any region of the linker is essential for fast inactivation. Deletion of the first 10 amino acids completely eliminated fast inactivation in the channel, whereas deletion of the last 10 amino acids had no substantial effect on inactivation. These results demonstrate that some residues in the amino end of the III-IV linker are critical for fast Na(+)-channel inactivation, but that the highly conserved positively charged and paired negatively charged residues are not essential.

A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.

The inward Na+ current underlying the action potential in nerve is terminated by inactivation. The preceding report shows that deletions within the intracellular linker between domains III and IV remove inactivation, but mutation of conserved basic and paired acidic amino acids has little effect. Here we show that substitution of glutamine for three clustered hydrophobic amino acids, Ile-1488, Phe-1489, and Met-1490, completely removes fast inactivation. Substitution of Met-1490 alone slows inactivation significantly, substitution of Ile-1488 alone both slows inactivation and makes it incomplete, and substitution of Phe-1489 alone removes inactivation nearly completely. These results demonstrate an essential role of Phe-1489 in Na(+)-channel inactivation. It is proposed that the hydrophobic cluster of Ile-1488, Phe-1489, and Met-1490 serves as a hydrophobic latch that stabilizes the inactivated state in a hinged-lid mechanism of Na(+)-channel inactivation.