Safety, Tolerability, and Effectiveness of Dextromethorphan/Quinidine for Pseudobulbar Affect Among Study Participants With Traumatic Brain Injury: Results From the PRISM-II Open Label Study

Background Dextromethorphan 20 mg / quinidine 10 mg (DM/Q) was approved to treat pseudobulbar affect (PBA) based on phase 3 trials conducted in participants with amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness, safety, and tolerability for PBA following stroke, dementia, or traumatic brain injury (TBI). Objective To report results from the TBI cohort of PRISM II, including a TBI-specific functional scale. Design Open-label trial evaluating twice-daily DM/Q over 90 days. Study participants Adults (n = 120) with a clinical diagnosis of PBA secondary to nonpenetrating TBI; stable psychiatric medications were allowed. Methods PRISM II was an open-label, 12-week trial enrolling adults with PBA secondary to dementia, stroke, or TBI. All study participants received DM/Q 20/10 mg twice daily. Study visits occurred at baseline and at day 30 and day 90. Setting 150 U.S. centers. Main Outcome Measurements Primary endpoint was change in Center for Neurologic Study–Lability Scale (CNS-LS) score from baseline to day 90. Secondary outcomes included PBA episode count, Clinical and Patient Global Impression of Change (CGI-C; PGI-C), Quality of Life–Visual Analog Scale (QOL-VAS), treatment satisfaction, Neurobehavioral Functioning Inventory (NFI), Patient Health Questionnaire (PHQ-9), and Mini Mental State Examination (MMSE). Results DM/Q-treated participants showed significant mean (SD) reductions in CNS-LS from baseline (day 30, –5.6 [5.2]; day 90, –8.5 [5.2]; both, P<.001). Compared with baseline, PBA episodes were reduced by 61.3% and 78.5% at days 30 and 90 (both, P<.001). At day 90, 78% and 73% of study participants had “much improved” or “very much improved” on the CGI-C and PGI-C. QOL-VAS scores were significantly reduced from baseline (–3.7 [3.3], P<.001). Mean (SD) PHQ-9 scores improved compared to baseline at day 30 (–3.2 [5.3], P<.001) and 90 (–5.2 [6.4], P<.001). NFI T scores were significantly improved (P<.001), whereas MMSE scores were unchanged. Adverse events (AEs) were consistent with the known DM/Q safety profile; the most common AE was diarrhea (8.3%). Conclusions DM/Q was well tolerated, and it significantly reduced PBA episodes in study participants with TBI. Changes in CNS-LS and PBA episode count were similar to changes with DM/Q in phase 3 trials

PRISM II: an open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury

BACKGROUND: Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI). METHODS: Participants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C). RESULTS: The study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, -7.7 [6.1]; P < .001, 95 % CI: -8.4, -7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, -8.2 [-9.4, -7.0]) and numerically exceeds the improvement seen with placebo in that study (-5.7 [-6.8, -4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were "much" or "very much" improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related. CONCLUSIONS: DM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01799941, registered on 25 February 2013

Characteristics and outcome of infants with candiduria in neonatal intensive care - a Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study

<p>Abstract</p> <p>Background</p> <p>There is limited information in the literature on the presentation and prognosis of candidal urinary tract infection (UTI) in infants in the neonatal intensive care unit (NICU).</p> <p>Methods</p> <p>This was a prospective cohort study performed in 13 Canadian NICUs. Infants with candidal UTI without extra-renal candidal infection at presentation were enrolled.</p> <p>Results</p> <p>Thirty infants fit the study criteria. Median birth weight and gestational age were 2595 grams (range 575-4255) and 35 weeks (range 24-41) with 10 infants being < 30 weeks gestation. The most common primary underlying diagnosis was congenital heart disease (n = 10). The median age at initial diagnosis was 16 days (range 6-84 days). Renal ultrasonography findings were compatible with possible fungal disease in 15 of the 26 infants (58%) in whom it was performed. Treatment was variable, but fluconazole and either amphotericin B deoxycholate or lipid-based amphotericin B in combination or sequentially were used most frequently. Extra-renal candidiasis subsequently developed in 4 infants. In 2 of these 4 infants, dissemination happened during prolonged courses of anti-fungal therapy. Three of 9 deaths were considered to be related to candidal infection. No recurrences of candiduria or episodes of invasive candidiasis following treatment were documented.</p> <p>Conclusion</p> <p>Candidal UTI in the NICU population occurs both in term infants with congenital abnormalities and in preterm infants, and is associated with renal parenchymal disease and extra-renal dissemination. A wide variation in clinical approach was documented in this multicenter study. The overall mortality rate in these infants was significant (30%). In one third of the deaths, <it>Candida </it>infection was deemed to be a contributing factor, suggesting the need for antifungal therapy with repeat evaluation for dissemination in infants who are slow to respond to therapy.</p

Developing and pre-testing a decision board to facilitate informed choice about delivery approach in uncomplicated pregnancy

<p>Abstract</p> <p>Background</p> <p>The rate of caesarean sections is increasing worldwide, yet medical literature informing women with uncomplicated pregnancies about relative risks and benefits of elective caesarean section (CS) compared with vaginal delivery (VD) remains scarce. A decision board may address this gap, providing systematic evidence-based information so that patients can more fully understand their treatment options. The objective of our study was to design and pre-test a decision board to guide clinical discussions and enhance informed decision-making related to delivery approach (CS or VD) in uncomplicated pregnancy.</p> <p>Methods</p> <p>Development of the decision board involved two preliminary studies to determine women's preferred mode of risk presentation and a systematic literature review for the most comprehensive presentation of medical risks at the time (VD and CS). Forty women were recruited to pre-test the tool. Eligible subjects were of childbearing age (18-40 years) but were not pregnant in order to avoid raising the expectation among pregnant women that CS was a universally available birth option. Women selected their preferred delivery approach and completed the Decisional Conflict Scale to measure decisional uncertainty before and after reviewing the decision board. They also answered open-ended questions reflecting what they had learned, whether or not the information had helped them to choose between birth methods, and additional information that should be included. Descriptive statistics were used to analyse sample characteristics and women's choice of delivery approach pre/post decision board. Change in decisional conflict was measured using Wilcoxon's sign rank test for each of the three subscales.</p> <p>Results</p> <p>The majority of women reported that they had learned something new (n = 37, 92%) and that the tool had helped them make a hypothetical choice between delivery approaches (n = 34, 85%). Women wanted more information about neonatal risks and personal experiences. Decisional uncertainty decreased (p < 0.001) and perceived effectiveness of decisions increased (p < 0.001) post-intervention.</p> <p>Conclusion</p> <p>Non-pregnant women of childbearing age were positive about the decision board and stated their hypothetical delivery choices were informed by risk presentation, but wanted additional information about benefits and experiences. This study represents a preliminary but integral step towards ensuring women considering delivery approaches in uncomplicated pregnancies are fully informed.</p

Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy

Purpose: Evaluate response of mismatch repair deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty dMMR rectal cancer patients were identified by immunohistochemistry and/or microsatellite instability analysis, with initial treatment response compared to a matched pMMR rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), 6 (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable to 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome (LS) with enrichment of germline MSH2 and MSH6 mutations when compared to 193 LS-associated colon cancer patients (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P &lt; .003). Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for LS in dMMR rectal cancer patients

Verbal Fluency Task

Code for a verbal fluency experiment on Pavlovia/Psychop