A Goffmanian analysis of impact of unclear professional identity and role negotiation of pharmacists in primary care: A multiple case study.

BACKGROUND: Professional identity and its development is a focus of research, education, and practice. But, there is a lack of how professional identity impacts changes in pharmacists' roles in practice, which are particularly prevalent in primary care teams. OBJECTIVES: This research uses Goffmanian theory, micro-sociologic interactional theory, to describe the outcomes of role negotiation in integrated primary care teams. METHODS: This is a multiple case study done per Yin, which used interviews and documents to collect data. Interviews used a storytelling format to gather information on the pharmacist's role and negotiation with their team. Four to six interviews were done in each case. Data was analyzed in an iterative manner using the Qualitative approach by Leuven including narrative reports being created for each case. RESULTS: Five cases were recruited but three cases were completed. In each case, the pharmacist was passive in role negotiation and allowed other actors to decide what tasks were of value. Likely this passivity was due to their professional identities: supportive and "not a physician". These identities led to a focus on the pharmacists' need to develop. This multi-case study demonstrated that pharmacists' professional identity led to passivity being valued and expected. Whether pharmacists self-limited, which has been previously seen, needs to be better defined. But unclear archetypes reduced tasks identified as unique to the pharmacist. CONCLUSION: Goffmanian theory highlighted a key success for future pharmacist role negotiation, a clear professional identity by both pharmacists and society, including team members. Until that occurs, there is a risk of underuse in primary care team settings.

Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease.

Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain-of-function mutations, end-organ damage and disease progression in ADTKD. Based on two prevalent missense UMOD mutations with divergent disease progression, we generated UmodC171Y and UmodR186S knock-in mice that showed strong allelic and gene dosage effects on uromodulin aggregates and activation of ER stress and unfolded protein and immune responses, leading to variable kidney damage. Deletion of the wild-type Umod allele in heterozygous UmodR186S mice increased the formation of uromodulin aggregates and ER stress. Studies in kidney tubular cells confirmed differences in uromodulin aggregates, with activation of mutation-specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased uromodulin aggregates. These studies substantiate the role of toxic aggregates as driving progression of ADTKD-UMOD, relevant for therapeutic strategies to improve clearance of mutant uromodulin.

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

Faecal immunochemical test for patients with 'high-risk' bowel symptoms: a large prospective cohort study and updated literature review.

BACKGROUND: We evaluated whether faecal immunochemical testing (FIT) can rule out colorectal cancer (CRC) among patients presenting with 'high-risk' symptoms requiring definitive investigation. METHODS: Three thousand five hundred and ninety-six symptomatic patients referred to the standard urgent CRC pathway were recruited in a multi-centre observational study. They completed FIT in addition to standard investigations. CRC miss rate (percentage of CRC cases with low quantitative faecal haemoglobin [f-Hb] measurement) and specificity (percentage of patients without cancer with low f-Hb) were calculated. We also provided an updated literature review. RESULTS: Ninety patients had CRC. At f-Hb < 10 µg/g, the miss rate was 16.7% (specificity 80.1%). At f-Hb < 4 µg/g, the miss rate was 12.2% (specificity 73%), which became 3.3% if low FIT plus the absence of anaemia and abdominal pain were considered (specificity 51%). Within meta-analyses of 9 UK studies, the pooled miss rate was 7.2% (specificity 74%) for f-Hb < 4 µg/g. DISCUSSION: FIT alone as a triage tool would miss an estimated 1 in 8 cases in our study (1 in 14 from meta-analysis), while many people without CRC could avoid investigations. FIT can focus secondary care diagnostic capacity on patients most at risk of CRC, but more work on safety netting is required before incorporating FIT triage into the urgent diagnostic pathway.

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness.

BACKGROUND: The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness. METHODS: A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants. RESULTS: We identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents. CONCLUSIONS: Biallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.

"Clearly they are in the circle of care, but . . .": A qualitative study exploring perceptions of personal health information sharing with community pharmacists in an integrated care model.

BACKGROUND: Ontario's Health Links approach to care is an integrated care model designed to optimize care for patients with complex needs. Currently, community pharmacists have no formalized role. This study aimed to explore stakeholders' perceptions about privacy and its impact on community pharmacists' involvement with integrated care models. METHODS: A qualitative study using semistructured telephone-based interviews was conducted. Participants worked in Ontario as pharmacists, providers in Health Links or team-based models or decision-makers in Health Links or health regions. Thematic analysis followed the Qualitative Analysis Guide of Leuven. RESULTS: Twenty-two participants were interviewed, and all but one commented on privacy or information sharing in integrating community pharmacists with integrated care models. The 4 themes identified were as follows: 1) what does the circle of care look like? 2) value of sharing information, 3) uncertainty of what information to share and 4) perceptions on how to share information. INTERPRETATION: The concerns surrounding privacy of personal health information and who is included in the circle of care represented an important barrier for integration. Enablers to mitigate privacy concerns included relationship building between community pharmacists, patients and other health care professionals and mutual access to information-sharing platforms such as electronic health records. CONCLUSION: Providers' and decision-makers' perceptions about community pharmacists and privacy affect information sharing and are incongruent with Ontario's Personal Health Information Protection Act. Education is needed for health care professionals on legislation, especially as health systems move towards integrated care models to improve care. Can Pharm J (Ott) 2020;153:xx-xx.

Understanding perceptions of involving community pharmacy within an integrated care model: a qualitative study.

BACKGROUND: Over the past several years, there has been more emphasis on integration within health care. Community pharmacy is often under-represented within integrated care models. This study explored stakeholder perceptions and enablers of including community pharmacy within an integrated care model. METHODS: A qualitative study was undertaken. Participants were recruited through professional networks and social media, as well as snowball recruitment from other participants. They included community pharmacists, clinicians, and decision-makers working in Ontario, Canada. Data were collected using telephone interviews completed with a semi-structured interview guide based on Consolidated Framework for Implementation Research from June to September 2018. Data were analysed inductively and deductively following the Qualitative Analysis Guide of Leuven. An additional theoretical framework (Rainbow Model of Integrated Care) was used to categorize enablers. RESULTS: Twenty-two participants were interviewed including nine pharmacists, seven clinicians, and six decision-makers. Three key themes were identified: 1) Positive value of including pharmacy in integrated care models; 2) One model does not fit all; and 3) Conflict of interest. Four key enablers were identified reflecting functional and normative factors: functional - 1) remuneration, 2) technology; normative - 3) engagement, and 4) relationships. While both functional and normative factors were discussed, the latter seemed to be more important to facilitate the inclusion of community pharmacy. Many participants characterized community pharmacists' lack of skills or confidence to provide patient care. CONCLUSIONS: This study confirms previously known views about concerns with community pharmacy's conflict of interest. However, discordant perceptions of conflict of interest and negative perceptions about capabilities of community pharmacy need to be addressed for successful integration. Normative enablers, such as culture, are likely important for organizational integration and require additional inquiry.

A new expression of immune checkpoint inhibitors' renal toxicity: when distal tubular acidosis precedes creatinine elevation.

The main manifestation of acute interstitial nephritis (AIN) due to immune checkpoint inhibitors is acute kidney injury. We report here a biopsy-proven AIN revealed by tubular acidosis. This case highlights that immune checkpoint inhibitor prescribers must be aware of electrolytic disorders since tubular dysfunction can precede serum creatinine increase and reveal renal toxicity.

Hepsin-mediated Processing of Uromodulin is Crucial for Salt-sensitivity and Thick Ascending Limb Homeostasis.

Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders. The luminal release and subsequent polymerization of uromodulin depend on its cleavage mediated by the serine protease hepsin. The biological relevance of a proper cleavage of uromodulin remains unknown. Here we combined in vivo testing on hepsin-deficient mice, ex vivo analyses on isolated tubules and in vitro studies on TAL cells to demonstrate that hepsin influence on uromodulin processing is an important modulator of salt transport via the sodium cotransporter NKCC2 in the TAL. At baseline, hepsin-deficient mice accumulate uromodulin, along with hyperactivated NKCC2, resulting in a positive sodium balance and a better adaptation to water deprivation. In conditions of high salt intake, defective uromodulin processing predisposes hepsin-deficient mice to a salt-wasting phenotype, with a decreased salt sensitivity. These modifications are associated with intracellular accumulation of uromodulin, endoplasmic reticulum-stress and signs of tubular damage. These studies expand the physiological role of hepsin and uromodulin and highlight the importance of hepsin-mediated processing of uromodulin for kidney tubule homeostasis and salt sensitivity.

The European Federation of Clinical Chemistry and Laboratory Medicine syllabus for postgraduate education and training for Specialists in Laboratory Medicine: version 5 - 2018.

Although laboratory medicine practise varies across the European Union's (EU) member states, the extent of overlap in scope is such that a common syllabus describing the education and training associated with high-quality, specialist practise can be identified. In turn, such a syllabus can help define the common set of skills, knowledge and competence in a Common Training Framework (CTF) for non-medical Specialists in Laboratory Medicine under EU Directive 2013/55/EU (The recognition of Professional Qualifications). In meeting the requirements of the directive's CTF patient safety is particularly enhanced when specialists seek to capitalise on opportunities for free professional migration across EU borders. In updating the fourth syllabus, the fifth expands on individual discipline requirements, new analytical techniques and use of statistics. An outline structure for a training programme is proposed together with expected responsibilities of trainees and trainers; reference is provided to a trainee's log book. In updating the syllabus, it continues to support national programmes and the aims of EU Directive 2013/55/EU in providing safeguards to professional mobility across European borders at a time when the demand for highly qualified professionals is increasing in the face of a disparity in their distribution across Europe. In support of achieving a CTF, the syllabus represents EFLM's position statement for the education and training that underpins the framework.

The tissue-engineered human cornea as a model to study expression of matrix metalloproteinases during corneal wound healing.

Corneal injuries remain a major cause of consultation in the ophthalmology clinics worldwide. Repair of corneal wounds is a complex mechanism that involves cell death, migration, proliferation, differentiation, and extracellular matrix (ECM) remodeling. In the present study, we used a tissue-engineered, two-layers (epithelium and stroma) human cornea as a biomaterial to study both the cellular and molecular mechanisms of wound healing. Gene profiling on microarrays revealed important alterations in the pattern of genes expressed by tissue-engineered corneas in response to wound healing. Expression of many MMPs-encoding genes was shown by microarray and qPCR analyses to increase in the migrating epithelium of wounded corneas. Many of these enzymes were converted into their enzymatically active form as wound closure proceeded. In addition, expression of MMPs by human corneal epithelial cells (HCECs) was affected both by the stromal fibroblasts and the collagen-enriched ECM they produce. Most of all, results from mass spectrometry analyses provided evidence that a fully stratified epithelium is required for proper synthesis and organization of the ECM on which the epithelial cells adhere. In conclusion, and because of the many characteristics it shares with the native cornea, this human two layers corneal substitute may prove particularly useful to decipher the mechanistic details of corneal wound healing.

A Cost-Effectiveness Analysis of Low-Risk Deliveries: A Comparison of Midwives, Family Physicians and Obstetricians.

OBJECTIVE: To investigate the cost-effectiveness of in-hospital obstetrical care by obstetricians (OBs), family physicians (FPs) and midwives (MWs) for delivery of low-risk obstetrical patients. METHODS: Cost-effectiveness analysis from the Ministry of Health perspective using a retrospective cohort study. The time horizon was from hospital admission of a low-risk pregnant patient to the discharge of the mother and infant. Costing data included human resource, intervention and hospital case-mix costs. Interventions measured were induction or augmentation of labour with oxytocin, epidural use, forceps or vacuum delivery and caesarean section. The outcome measured was avoidance of transfer to a neonatal intensive care unit (NICU). Model results were tested using various types of sensitivity analyses. FINDINGS: The mean maternal age by provider groups was 29.7 for OBs, 29.8 for FPs and 31.2 for MWs - a statistically higher mean for the MW group. The MW deliveries had lower costs and better outcomes than FPs and OBs. FPs also dominated OB.s The differences in cost per delivery were small, but slightly lower in MW ($5,102) and FP ($5,116) than in OB ($5,188). Avoidance of transfer to an NICU was highest for MW at 94.0% (95% CI: 91.0-97.0), compared with 90.2% for FP (95% CI: 88.2-92.2) and 89.6% for OB (95% CI: 88.6-90.6). The cost-effectiveness of the MW group is diminished by increases in compensation, and the cost-effectiveness of the FP group is sensitive to changes in intervention rates and costs. CONCLUSIONS: The MW strategy was the most cost-effective in this hospital setting. Given data limitations to further examine patient characteristics between groups, the overall conservative findings of this study support investments and better integration for MWs in the current system.

Functional Impact of Collagens on the Activity Directed by the Promoter of the α5 Integrin Subunit Gene in Corneal Epithelial Cells.

PURPOSE: The early step of corneal wound healing is characterized by the massive production of fibronectin (FN), whose secretion is progressively replaced by collagens from the basal membrane as wound healing proceeds. Here, we examined whether expression of the gene encoding the α5 subunit from the FN-binding integrin α5ß1 changes as corneal epithelial cells (CECs) are cultured in the presence of collagen type I (CI) or type IV (CIV). METHODS: Responsiveness of the α5 gene toward collagen was determined by transfection of α5 promoter/chloramphenicol acetyltransferase (CAT) plasmids into rabbit and human CECs cultured on BSA or collagens. Electrophoretic mobility shift assays and Western blots were used to monitor the transcription factors required for basal α5 gene transcription in the presence of collagens. Gene profiling on microarrays was used to determine the impact of collagens on the patterns of genes expressed by CECs. RESULTS: All collagen types repressed the full-length α5/CAT promoter activity in confluent CECs. A moderate increase was observed in subconfluent rabbit CECs grown on CIV but not on CI. These collagen-dependent regulatory influences also correlated with alterations in the transcription factors Sp1/Sp3, NFI, and AP-1 that ensure α5 gene basal transcription. Microarray analyses revealed that CI more profoundly altered the pattern of genes expressed by human CECs than CIV. CONCLUSIONS: Collagens considerably suppressed α5 gene expression in CECs, suggesting that during wound healing, they may interfere with the influence FN exerts on CECs by altering their adhesive and migratory properties through a mechanism involving a reduction in α5 gene expression.

Treating recurrent postmenopausal vasomotor symptoms in a patient with a positive family history for breast cancer.

OBJECTIVE: To report a case of recurrent hot flashes unresponsive to gabapentin in a postmenopausal patient with a positive family history of breast cancer. CASE SUMMARY: A 69-year-old Caucasian female experienced a recurrence of debilitating hot flashes for the past eight months. More recently, she failed a two-month trial of gabapentin 600 mg by mouth at bedtime after she previously received effective hormone replacement therapy (HRT) seven years ago with near-complete resolution of her symptoms. The patient had a sister and a niece who developed breast cancer in their 40s. DISCUSSION: The treatment of postmenopausal hot flashes in a patient with a positive family history of breast cancer represents a clinical challenge for many clinicians. This case is an example in which gabapentin was ineffective in the treatment of severe hot flashes in a postmenopausal woman. The risks and benefits of HRT compared with nonhormonal alternatives were assessed. CONCLUSION: In this case, a two-month trial of gabapentin 600 mg/day failed to demonstrate efficacy in reducing the severity, frequency, and duration of hot flashes. Controlled trials are necessary to evaluate the safety and efficacy of other therapeutic alternatives.

Expression of the α5 integrin gene in corneal epithelial cells cultured on tissue-engineered human extracellular matrices.

The integrin α5ß1 plays a major role in corneal wound healing by promoting epithelial cell adhesion and migration over the fibronectin matrix secreted as a cellular response to corneal damage. Expression of α5 is induced when rabbit corneal epithelial cells (RCECs) are grown in the presence of fibronectin. Here, we examined whether α5 expression is similarly altered when RCECs or human corneal epithelial cells (HCECs) are grown on a reconstructed stromal matrix used as an underlying biomaterial. Mass spectrometry and immunofluorescence analyses revealed that the biomaterial matrix produced by culturing human corneal fibroblasts with ascorbic acid (ECM/35d) contains several types of collagens, fibronectin, tenascin and proteoglycans. Results from transfection of CAT/α5-promoter plasmids, Western blot and EMSA analyses indicated that ECM/35d significantly increase expression of α5 in HCECs as a result of alteration in the expression and DNA binding of the transcription factors NFI, Sp1, AP-1 and PAX6. The biological significance of this biomaterial substitute on the expression of the α5 gene may therefore contribute to better understand the function played by the α5ß1 integrin during corneal wound healing.

A Pharmacist-Led Point-of-Care INR Clinic: Optimizing Care in a Family Health Team Setting.

Purpose. Monitoring patients' international normalized ratio (INR) within a family medicine setting can be challenging. Novel methods of doing this effectively and in a timely manner are important for patient care. The purpose of this study was to determine the effectiveness of a pharmacist-led point-of-care (POC) INR clinic. Methods. At a community-based academic Family Health Team in Toronto, Canada, charts of patients with atrial fibrillation managed by a pharmacist with usual care (bloodtesting at lab and pharmacist follow up of INR by phone) from February 2008 to April 2008 were compared with charts of patients attending a weekly POC INR clinic from February 2010 to April 2010. Time in therapeutic range (TTR) was measured for both groups. Results. 119 patient charts were reviewed and 114 had TTR calculated. After excluding patients with planned inconsistent Coumadin use (20), such as initiating Coumadin treatment or stopping for a surgical procedure, the mean TTR increased from 64.41% to 77.09% with the implementation of the POC clinic. This was a statistically significant difference of 12.68% (CI: 1.18, 24.18; P = 0.03). Conclusion. A pharmacist-led POC-INR clinic improves control of anticoagulation therapy in patients receiving warfarin and should be considered for implementation in other family medicine settings.