Nevin Manimala

Int J Clin Pharm. 2021 Jun 14. doi: 10.1007/s11096-021-01296-1. Online ahead of print.

ABSTRACT

Background Studies have highlighted advancing clinical pharmacy practice in Qatar. Objective To explore pharmacists’ aspirations and readiness to implement pharmacist prescribing. Setting Hamad Medical Corporation (HMC), the main provider of secondary and tertiary care. Method A sequential explanatory mixed-methods design. Questionnaire items were derived from the Consolidated Framework of Implementation Research (CFIR), in domains of: awareness/support; readiness; implementation; and facilitators and barriers. Following piloting, all pharmacists (n = 554) were invited to participate. Questionnaire data were analysed using descriptive and inferential statistics with principal component analysis of attitudinal items. Focus groups were recorded, transcribed and analysed using the Framework Approach. Main outcome measure Aspirations and readiness to implement pharmacist prescribing. Results The response rate was 62.8% (n = 348), with respondents highly supportive of implementation in Qatar (median 4, scale 0-5, extremely supportive). The majority (64.9%, n = 226) considered themselves ready, particularly those more senior (p < 0.05) and classifying themselves innovative (p < 0.01). Outpatient (72.9%, n = 221 agreeing) and inpatient (71.1%, n = 218 agreeing) HMC settings were those perceived as being most ready. PCA identified 2 components, with ‘personal attributes’ being more positive than ‘prescribing support’. Facilitators were access to records, organizational/management support and the practice environment, with physician resistance and scope of practice as barriers. Focus groups provided explanation, with themes in CFIR domains of innovation characteristics, characteristics of individuals and the inner setting. Conclusion HMC pharmacists largely aspire, and consider themselves ready, to be prescribers with inpatient and outpatient settings most ready. CFIR domains and constructs identified as facilitators and barriers should be focus for implementation.

PMID:34125372 | DOI:10.1007/s11096-021-01296-1

Cardiovasc Drugs Ther. 2021 Jun 14. doi: 10.1007/s10557-021-07210-1. Online ahead of print.

ABSTRACT

PURPOSE: In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use.

METHODS: We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO’s VigiBase, FAERS, and EMA’s EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA’s OpenVigil 2.0.

RESULTS: Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice.

CONCLUSION: With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.

PMID:34125356 | DOI:10.1007/s10557-021-07210-1

Ann Surg Oncol. 2021 Jun 14. doi: 10.1245/s10434-021-10148-1. Online ahead of print.

ABSTRACT

BACKGROUND: Nearly one-third of patients with inflammatory breast cancer (IBC) present with de novo stage IV disease. There are limited data on frequency and clinical outcomes of contralateral axillary metastasis (CAM) in IBC with no consensus diagnostic and treatment guidelines.

PATIENTS AND METHODS: Frequency of synchronous CAM was calculated in unilateral IBC patients at a single center (10/2004-6/2019). Clinicopathologic variables, diagnostic evaluation, treatment received, and overall survival (OS) were assessed and compared.

RESULTS: Of 588 unilateral IBC patients, 49 (8.3%) had synchronous CAM. Of these, 32 (65.3%) also presented with metastatic disease at another distant site. CAM was not associated with age, tumor laterality, breast cancer subtype, grade, or cN stage (p > 0.05). The sensitivity/specificity to detect CAM was as follows: mammography (18.2%/99.2%), ultrasound (92.3%/95.5%), PET (90.1/99.1%), and MRI (76.0%/98.6%). Following systemic therapy, 22 patients had contralateral axillary surgery, and 18 received adjuvant contralateral nodal radiation. On multivariable analysis including tumor receptor subtypes, patients with stage IV-isolated CAM has statistically similar survival to stage III patients (HR 1.37, 95% CI 0.70-2.69, p = 0.36). Patients with Stage IV non-CAM (HR 2.18, 95% CI 1.66-2.85, p < 0.001) and stage IV-CAM plus other distant metastasis (HR 2.57, 95% CI 1.59-4.16, p < 0.001) had higher risk of death (reference: stage III disease).

CONCLUSIONS: CAM in IBC was diagnosed in 8.3% of patients at presentation and was best identified by ultrasound and PET. We recommend routine contralateral axillary ultrasound as part of staging for all IBC patients. Diagnosis of CAM is a key first step toward much-needed prospective clinical trials evaluating management and outcomes of CAM in IBC.

PMID:34125346 | DOI:10.1245/s10434-021-10148-1

J Psycholinguist Res. 2021 Jun 14. doi: 10.1007/s10936-021-09784-1. Online ahead of print.

ABSTRACT

It is unknown how self-relevance is dependent on emotional salience. Emotional salience encompasses an individual’s degree of attraction or aversion to emotionally-valenced information. The current study investigated the interconnection between self and salience through the evaluation of emotional valence and self-relevance. 56 native Dutch participants completed a questionnaire assessing valence, intensity, and self-relevance of 552 Dutch nouns and verbs. One-way repeated-measures ANCOVA investigated the relationship between valence and self, age and gender. Repeated-measures ANCOVA also tested the relationship between valence and self with intensity ratings and effects of gender and age. Results showed a significant main effect of valence for self-relevant words. Intensity analyses showed a main effect of valence but not of self-relevance. There were no significant effects of gender and age. The most important finding presents that self-relevance is dependent on valence. These findings concerning the relationship between self and salience opens avenues to study an individual’s self-definition.

PMID:34125312 | DOI:10.1007/s10936-021-09784-1

Graefes Arch Clin Exp Ophthalmol. 2021 Jun 14. doi: 10.1007/s00417-021-05257-2. Online ahead of print.

ABSTRACT

PURPOSE: To compare surgical outcomes between patients who underwent Baerveldt glaucoma implantation versus trabeculectomy (TLE) for the treatment of neovascular glaucoma.

METHODS: We performed a prospective, randomized, controlled clinical trial at Hiroshima University and Tsukazaki Hospital, Japan. Patients were randomized to Baerveldt glaucoma implantation (23 patients) or TLE (27 patients). The primary outcome measure was the rate of intraocular-pressure control. Secondary outcome measures included complications and interventions. We defined “failure” as intraocular pressure ≥ 22 mmHg or < 20% reduction from baseline pressure, on two consecutive follow-up visits; need for additional glaucoma surgery; vision-threatening complications; or loss of light perception. Kaplan-Meier analysis was used to determine surgical success rates. Postoperative complications and interventions were compared between the two groups with Pearson Chi-square tests.

RESULTS: There were no significant differences in demographic or ocular characteristics between the treatment groups at baseline. The postoperative follow-up was 26.6 ± 19.4 months in the Baerveldt group and 27.3 ± 20.1 months in the TLE group. There were no statistical differences (Mann-Whitney nonparametric tests with Bonferroni correction) in postoperative intraocular pressure measured at 6-month intervals. Success rates were 59.1 and 61.6% at 1-year after Baerveldt glaucoma implantation and TLE, respectively. Kaplan-Meier analysis showed no significant difference in success between groups (P = 0.71, log-rank test). Medication use, visual acuity, and interventions were similar between groups. Thirteen late postoperative complications developed in the Baerveldt glaucoma implantation group and four complications developed in the TLE group. Tube exposure was the most common late complication.

CONCLUSION: These two procedures produced similar surgical success, intraocular-pressure reductions, visual acuity, and number of medications at the last visit. The TLE group showed smaller numbers of late complications and patients who lost more than two lines of visual acuity. Therefore, TLE might be a safer and better way to treat patients with neovascular glaucoma.

PMID:34125289 | DOI:10.1007/s00417-021-05257-2

CVIR Endovasc. 2021 Jun 14;4(1):51. doi: 10.1186/s42155-021-00234-6.

ABSTRACT

BACKGROUND: This study aimed to assess the error of different registration techniques and imaging modalities for fusion imaging of the aorta in a standardized setting using a anthropomorphic body phantom.

MATERIALS AND METHODS: A phantom with the 3D printed vasculature of a patient suffering from an infrarenal aortic aneurysm was constructed. Pulsatile flow was generated via an external pump. CTA/MRA of the phantom was performed, and a virtual 3D vascular model was computed. Subsequently, fusion imaging was performed employing 3D-3D and 2D-3D registration techniques. Accuracy of the registration was evaluated from 7 right/left anterior oblique c-arm angulations using the agreement of centerlines and landmarks between the phantom vessels and the virtual 3D virtual vascular model. Differences between imaging modalities were assessed in a head-to-head comparison based on centerline deviation. Statistics included the comparison of means ± standard deviations, student’s t-test, Bland-Altman analysis, and intraclass correlation coefficient for intra- and inter-reader analysis.

RESULTS: 3D-3D registration was superior to 2D-3D registration, with the highest mean centerline deviation being 1.67 ± 0.24 mm compared to 4.47 ± 0.92 mm. The highest absolute deviation was 3.25 mm for 3D-3D and 6.25 mm for 2D-3D registration. Differences for all angulations between registration techniques reached statistical significance. A decrease in registration accuracy was observed for c-arm angulations beyond 30° right anterior oblique/left anterior oblique. All landmarks (100%) were correctly positioned using 3D-3D registration compared to 81% using 2D-3D registration. Differences in accuracy between CT and MRI were acceptably small. Intra- and inter-reader reliability was excellent.

CONCLUSION: In the realm of registration techniques, the 3D-3D method proved more accurate than did the 2D-3D method. Based on our data, the use of 2D-3D registration for interventions with high registration quality requirements (e.g., fenestrated aortic repair procedures) cannot be fully recommended. Regarding imaging modalities, CTA and MRA can be used equivalently.

PMID:34125287 | DOI:10.1186/s42155-021-00234-6

Eur Arch Otorhinolaryngol. 2021 Jun 14. doi: 10.1007/s00405-021-06937-9. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this study was to investigate the changes in voice nasality after septoplasty and turbinate hypertrophy reduction and to evaluate the effect of these changes on patients’ voice-related quality of life.

METHODS: Sixty patients with nasal obstruction symptoms caused by septal deviation and inferior turbinate hypertrophy who underwent septoplasty and inferior turbinate hypertrophy reduction and 25 healthy controls were included. Active anterior rhinomanometry and acoustic rhinometry were utilized for the evaluation of nasal patency and nasometry was used for quantitative assessment of nasalance. All participants completed validated questionnaires for assessing nasal obstruction symptom severity, psychological status and the impact of voice performance on their quality of life preoperatively and 6 months after septoplasty.

RESULTS: Patients presented preoperatively statistically significantly lower nasalance scores and higher VHI scores than controls (p < 0.05). Septoplasty and inferior turbinate hypertrophy reduction led to improvement of nasalance for the nasal text and the physical subscale of the VHI scores. Postoperatively, there were no statistically significant differences in nasalance and VHI scores between patients and controls. Significant correlations were found only for the baseline and the postoperative nasalance scores for the nasal text and the total nasal cavity volume (p < 0.05). Postoperatively, patients who presented significant improvement of nasal obstruction symptoms and resolution of stress levels were more likely to positively evaluate the impact of their voice quality on their daily life (OR: 2.32, 95% CI 1.08-5.15, p = 0.041 and OR: 3.06, 95% CI 1.15-7.04, p = 0.038, respectively).

CONCLUSION: Septoplasty and inferior turbinate hypertrophy reduction may increase the nasal resonance, but in the long term, this change appears not to be significant enough. The severity of nasal obstruction symptoms and psychological status mainly affect the patients’ perceptual assessment regarding the effect of voice performance on their quality of life.

PMID:34125283 | DOI:10.1007/s00405-021-06937-9

J Neurol. 2021 Jun 14. doi: 10.1007/s00415-021-10635-1. Online ahead of print.

ABSTRACT

OBJECTIVE: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare disease characterized by rapid neuropathic progression. In pivotal studies of gene-silencing treatments, the modified Neuropathy Impairment Score + 7 tests (mNIS + 7) and Norfolk-Quality of Life (QOL)-Diabetic Neuropathy (DN) questionnaire assessed treatment impact on neuropathic progression. Establishing responder definition (RD) thresholds for these measures would enable evaluation of clinically meaningful treatment benefit.

METHODS: mNIS + 7 and Norfolk-QOL-DN were administered at baseline and week 65 to 165 adults with ATTRv-PN receiving inotersen (n = 106) or placebo (n = 59) in the NEURO-TTR study. Anchor-based approaches for estimating RD thresholds were used for Norfolk QOL-DN, while distribution-based approaches were used for both measures. Responders were patients with a score change < RD, indicating improvement or stabilization (i.e., no clinically meaningful progression). Odds ratios (ORs) and Fisher’s exact tests compared proportions of responders by treatment.

RESULTS: The mean RD estimates were 12.2 points and 8.8 points for mNIS + 7 and Norfolk QOL-DN, respectively. The proportions of patients whose change in score indicated improvement or stabilization were statistically significantly larger for inotersen than placebo for all estimated RD thresholds for mNIS + 7 (64-86% responders for inotersen vs. 27-46% for placebo, ORs = 3.8-7.2, ps < 0.001) and Norfolk QOL-DN (66-81% vs. 35-56%, ORs = 2.4-3.6, ps < 0.05).

DISCUSSION: Establishing RD thresholds for these instruments enables evaluation of clinically relevant and individual-level treatment benefit on neuropathic progression. Across RDs estimated using multiple methods, a higher proportion of patients receiving inotersen than placebo showed improved or stabilized neuropathic progression at week 65.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.

PMID:34125267 | DOI:10.1007/s00415-021-10635-1

Arch Orthop Trauma Surg. 2021 Jun 14. doi: 10.1007/s00402-021-03991-0. Online ahead of print.

ABSTRACT

INTRODUCTION: The risk factors for a second nonsimultaneous hip fracture are unclear, and in general, it is empirically assumed that they are similar to those associated with the first hip fracture. We aimed to determine the incidence of a second hip fracture and define the characteristics of the patients sustaining the event in a prospective cohort study in a Spanish population.

MATERIALS AND METHODS: We conducted a multicentric, prospective cohort study in a representative sample of 45 hospitals from 15 autonomic regions in Spain. In total, the study included 994 patients. One hundred and one patients presented a nonsimultaneous contralateral hip fracture, constituting the intervention group. The remaining 893 patients presenting with a hip fracture formed the control group. The main outcome measures of this study were sociodemographic characteristics of the patient, comorbid conditions, and baseline and postfracture clinical outcomes (inpatient complications and acute mortality).

RESULTS: The key fracture risk factors were a history of fragility fractures, the need for assistance when walking outdoors and a history of falls. There were no associations between the groups in any of the common fragility risk factors, including rheumatoid arthritis, secondary osteoporosis, or steroid consumption. The results showed that patients suffering a nonsimultaneous hip fracture had an increased risk of mortality after discharge compared with the control group.

CONCLUSION: A nonsimultaneous second hip fracture leads to a near-significant increase in four-month mortality. In our study, this fracture was associated with a history of falls, prior fragility fractures, and the need for a walking aid.

PMID:34125250 | DOI:10.1007/s00402-021-03991-0

Acta Neuropathol. 2021 Jun 14. doi: 10.1007/s00401-021-02325-z. Online ahead of print.

ABSTRACT

Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1-2% of all cases of Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2-either in its kinase domain (e.g. G2019S) with modest effect or its ROC-COR GTPase domain (e.g. R1441G/H) with large effect on LRRK2 kinase activity. We have previously reported assays to interrogate LRRK2 kinase pathway activity in human bio-samples measuring phosphorylation of its endogenous substrate Rab10, that mirrors LRRK2 kinase activation status. Here, we isolated neutrophils from fresh peripheral blood from 101 participants including 42 LRRK2 mutation carriers (21 with the G2019S and 21 with the R1441G mutations), 27 patients with idiopathic PD, and 32 controls. Using a dual approach, LRRK2 dependent Rab10 phosphorylation at Threonine 73 (pRab10^Thr73) was measured by quantitative multiplexed immunoblotting for pRab10^Thr73/total Rab10 as well as targeted mass-spectrometry for absolute pRab10^Thr73 occupancy. We found a significant over fourfold increase in pRab10^Thr73 phosphorylation in carriers of the LRRK2 R1441G mutation irrespective of clinical disease status. The effect of the LRRK2 G2019S mutation did not reach statistical significance. Furthermore, we show that LRRK2 phosphorylation at Serine 935 is not a marker for LRRK2 kinase activity in human neutrophils. When analysing pRab10^Thr73 phosphorylation in post-mortem brain samples, we observed overall high variability irrespective of clinical and LRRK2 mutation status and attributed this mainly to the adverse effect of the peri- and post-mortem period on the stability of posttranslational modifications such as protein phosphorylation. Overall, in vivo LRRK2 dependent pRab10^Thr73 phosphorylation in human peripheral blood neutrophils is a specific, robust and promising biomarker for significant LRRK2 kinase hyperactivation, as with the LRRK2 R1441G mutation. Additional readouts and/or assays may be needed to increase sensitivity to detect modest LRRK2 kinase activation, as with the LRRK2 G2019S mutation. Our assays could be useful for patient stratification and target engagement studies for LRRK2 kinase inhibitors.

PMID:34125248 | DOI:10.1007/s00401-021-02325-z